Soft steroids having anti-inflammatory activity

ABSTRACT

The invention provides novel soft steroidal anti-inflammatory agents, pharmaceutical compositions containing said agents, and methods of administering same to mammals in the treatment of inflammation. Preferred compounds of the invention include haloalkyl 17α-alkoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylates and the corresponding Δ 1 ,4 compounds, optionally bearing 6α- and/or 9α-fluorine and 16α- or 16β-methyl substituents. Especially preferred compounds include haloalkyl 17α-alkoxycarbonyloxy-9α-fluoro-11β-hydroxy-16-methylandrosta-1,4-dien-3-one-17β-carboxylates.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 626,535,filed June 29, 1984, now abandoned, which is a continuation of Ser. No.418,458, filed Sept. 18, 1982, now abandoned, which is acontinuation-in-part of Ser. No. 265,785, filed May 21, 1981, nowabandoned, which was a continuation-in-part of Ser. No. 168,453, filedJuly 10, 1980, now abandoned. The said earlier applications areexpressly incorporated by reference herein in their entireties andrelied upon.

TECHNICAL FIELD OF THE INVENTION

The invention relates to novel soft steroids having anti-inflammatoryactivity, pharmaceutical compositions containing said soft steroids,novel chemical intermediates useful in the preparation of the steroids,and methods of administering said steroids to mammals in the treatmentof inflammation.

BACKGROUND ART

Successful predictions on a rational basis of the biological activity ofcompounds leading to new drugs are the main objective of drug designers.This has usually been achieved by considering a known bioactive moleculeas the basis for structural modifications, either by the group orbiofunctional moieties approach or by altering the overallphysical-chemical properties of the molecule. Thus, the main aim hasbeen to design, synthesize, and test new compounds structurallyanalogous to the basic bioactive molecule which have, however, improvedtherapeutic and/or pharmacokinetic properties. Although "vulnerable"moieties have been identified as the ones whose role is thebioinactivation or metabolic elimination of the drug after it hasperformed its role, little or no attention has been paid in thedrug-design process to the rational design of the metabolic dispositionof the drugs. This has been the case despite the fact that the toxicityof a number of bioactive molecules is due to their increased eliminationhalf-life, stability, or other factors introduced during the design ofincreasing their activity. Drugs and particularly their metabolicprocesses contribute to the various toxic processes by formation ofactive metabolites. The phenomenon of metabolic activation to reactiveintermediates which covalently bind to tissue macromolecules is theinitial step in cell damage. It is also clear that the most toxicmetabolites will not survive long enough to be excreted and identified;thus, studies of the stable metabolites may provide misleadinginformation.

It is clear that, in order to prevent and/or reduce toxicity problemsrelated to drugs, the metabolic disposition of the drugs should beconsidered at an early stage of the drug-design process. This is trueparticularly when one considers that the body can attack and alterchemically quite stable structures and that, even if a drug is 95%excreted unchanged, the unaccounted small portion can, and most likelywill, cause toxicity.

"Soft drugs" can be defined as biologically active chemical compounds(drugs) which might structurally resemble known active drugs (softanalogues) or could be entirely new types of structures, but which areall characterized by a predictable in vivo destruction (metabolism) tonontoxic moieties, after they achieve their therapeutic role. Themetabolic disposition of the soft drugs takes place with a controllablerate in a predictable manner.

The present inventor has found five major classes of soft drugs. One ofthe most useful classes was termed the "inactive metabolite" approachwhich can be advantageously employed to design especially valuable "softdrugs". This approach starts with a known inactive metabolite of a drugor a drug class; followed by modifying the metabolite to resemblestructurally (isosteric and/or isoelectronic) the active drug (i.e.,activation); and designing the metabolism of the activated species tolead to the starting inactive metabolite after achieving the desiredtherapeutic role, without the formation of toxic intermediates (i.e.,predictable metabolism). The "inactive metabolite" approach furtherallows controlling the rate of metabolism and pharmacokinetic propertiesby molecular manipulation in the activation stage. Also, if no usefulinactive metabolite is known, one can be designed by the introduction oftransporting groups in noncritical structural parts.

SUMMARY OF THE INVENTION

The present inventor has now applied his inactive metabolite approach tothe case of the natural and synthetic glucocorticosteroids and hasdesigned the soft steroidal anti-inflammatory agents of the presentinvention, beginning with the known inactive natural metabolites of theglucocorticosteroids. Thus, for example, in the case of hydrocortisone,one of its major, inactive metabolites, cortienic acid, i.e.,11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid, has been usedas a starting point and activated by the introduction of suitablenon-toxic 17α- and 17β-substituents, which activated derivatives willcleave in vivo, after accomplishment of their therapeutic role, to thestarting inactive metabolite and other nontoxic moieties.

In accord with the foregoing, the present invention provides novel softsteroids having anti-inflammatory activity, said steriods having thestructural formula ##STR1## wherein:

R₁ is C₁ -C₁₀ alkyl; C₂ -C₁₀ (monohydroxy or polyhydroxy)alkyl; C₁ -C₁₀(monohalo or polyhalo)alkyl; or --CH₂ COOR₆ wherein R₆ is unsubstitutedor substituted C₁ -C₁₀ alkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl orC₂ -C₁₀ alkenyl, the substituents being selected from the groupconsisting of halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl,lower alkylsulfonyl, ##STR2## or R₆ is unsubstituted or substitutedphenyl or benzyl, the substituents being selected from the groupconsisting of lower alkyl, lower alkoxy, halo, carbamoyl, loweralkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(loweralkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(loweralkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and loweralkylsulfonyl; or R₁ is --CH₂ CONR₇ R₈ wherein R₇ and R₈, which can bethe same or different, are each hydrogen, lower alkyl, C₃ -C₈cycloalkyl, phenyl or benzyl, or R₇ and R₈ are combined such that --NR₇R₈ represents the residue of a saturated monocyclic secondary amine; orR₁ is unsubstituted or substituted phenyl or benzyl, the substituentsbeing selected from the group of phenyl and benzyl substituents definedhereinabove with respect to R₆ ; or R₁ is ##STR3## wherein Y is --S--,--SO--, --SO₂ -- or --O-- and R₉ is hydrogen, lower alkyl or phenyl, orR₉ and the lower alkyl group adjacent to Y are combined so that R₁ is acyclic system of the type ##STR4## wherein Y is defined as above and thealkylene group contains 3 to 10 carbon atoms, of which at least 3 and nomore than 6 are ring atoms; or R₁ is ##STR5## wherein R₆ is defined ashereinabove and R₁₀ is hydrogen, lower alkyl, phenyl or haloalkyl;

R₂ is unsubstituted or substituted C₁ -C₁₀ alkyl, C₃ -C₈ cycloalkyl, C₃-C₈ cycloalkenyl or C₂ -C₁₀ alkenyl, the substituents being selectedfrom the group consisting of halo, lower alkoxy, lower alkylthio, loweralkylsulfinyl, lower alkylsulfonyl, ##STR6## or R₂ is unsubstituted orsubstituted phenyl or benzyl, the substituents being selected from thegroup consisting of lower alkyl, lower alkoxy, halo, carbamoyl, loweralkoxycarbonyl, lower alkanoyloxy, lower haloalkyl, mono(loweralkyl)amino, di(lower alkyl)amino, mono(lower alkyl)carbamoyl, di(loweralkyl)carbamoyl, lower alkylthio, lower alkylsulfinyl and loweralkylsulfonyl;

R₃ is hydrogen, α-hydroxy, β-hydroxy, α-methyl, β-methyl, ═CH₂, or α- or##STR7## wherein R₂ is identical to R₂ as defined hereinabove; R₄ ishydrogen, fluoro or chloro;

R₅ is hydrogen, fluoro, chloro or methyl;

X is --O-- or --S--;

Z is carbonyl or β-hydroxymethylene;

and the dotted line in ring A indicates that the 1,2-linkage issaturated or unsaturated.

A group of preferred compounds of formula (I) consists of those

wherein:

R₁ is C₁ -C₆ alkyl; C₁ -C₆ (monohalo or polyhalo)alkyl; --CH₂ COOR₆wherein R₆ is C₁ -C₆ alkyl; --CH₂ --Y--(C₁ -C₆ alkyl) wherein Y is--S--, --SO--, --SO₂ -- or --O--; or ##STR8## wherein R₆ ' is C₁ -C₆alkyl or phenyl; R₂ is C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, phenyl, benzylor C₁ -C₆ (monohalo or polyhalo)alkyl;

R₃ is hydrogen, α-hydroxy, α-methyl, β-methyl or ##STR9## wherein R₂ isidentical to R₂ as defined hereinabove; R₄ is hydrogen or fluoro;

R₅ is hydrogen or fluoro;

Z is β-hydroxymethylene;

and X and the dotted line in ring A are defined as hereinabove.

The invention further provides anti-inflammatory quaternary ammoniumsalts of selected compounds of formula (I), as discussed in furtherdetail below. Novel intermediates to the compounds of formula (I), e.g.,the corresponding compounds wherein R₁ is hydrogen, are provided also.

The soft steroids of formula (I) and quaternary ammonium salts thereofare extremely potent local anti-inflammatory agents; however, by virtueof the fact that their facile in vivo destruction leads only to theinactive steroidal metabolite, the present compounds have far lesssystemic activity than the known glucocorticosteroids from whoseinactive metabolites they are derived. Indeed, many of the compounds ofthe present invention are entirely devoid of systemic activity. Suchminimal-- or non-existent-- systemic activity means that the compoundsof the present invention can be used in the local (e.g., topical)treatment of inflammatory conditions without the serious systemic sideeffects which attend use of the known glucocorticosteroids.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

With respect to the various groups encompassed by the generic terms usedhere and throughout this specification, the following definitions andexplanations are applicable:

The alkyl, alkenyl and alkylene groupings can be straight orbranched-chain groups containing the aforementioned number of carbonatoms. Likewise, the alkyl portions of the alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkanoyloxy, haloalkyl,monoalkylamino, dialkylamino, monoalkylcarbamoyl and dialkylcarbamoylgroupings each can be straight or branched-chain. The term "lower" usedin conjunction with any of those groupings or in conjunction with"alkyl" is intended to indicate that each alkyl portion therein cancontain 1 to 8 carbon atoms.

Specific examples of alkyl radicals encompassed by formula (I), whetheras specific values for R₁ or R₂, or as a portion of a R₁, R₂, or R₃group, include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl andoctyl and their branched-chain isomers, as well as their straight andbranched-chain higher homologues in the instances where "alkyl" cancontain more than 8 carbon atoms. The alkenyl radicals can beexemplified by vinyl, propenyl and butenyl. Illustrative of thecycloalkyl and cycloalkenyl radicals are cyclopentyl, cyclohexyl,cyclopentenyl and cyclohexenyl. The alkylene moieties are typified bytimethylene, tetramethylene and the like.

The alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl,alkanoyloxy, monoalkylamino, dialkylamino, monoalkylcarbamoyl anddialkylcarbamoyl ##STR10## respectively, wherein alkyl is ashereinbefore defined and exemplified.

With respect to the structural variables encompassed by the group ofpreferred compounds of formula (I) identified hereinabove, the term "C₁-C₆ alkyl" is used to refer to a straight or branched-chain alkyl grouphaving 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and thelike. In addition, the term "C₁ -C₆ (monohalo or polyhalo)alkyl" is usedto refer to a straight or branched-chain alkyl group having 1 to 6carbon atoms substituted with from 1 to 3 halogen atoms, the term"halogen" as used herein including a chlorine atom, a bromine atom, aniodine atom or a fluorine atom. Specific examples of the contemplatedmonohaloalkyl and polyhaloalkyl groups include chloromethyl,dichloromethyl, trichloromethyl, bromomethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1-chloroethyl,2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl,1,2-dichloroethyl, 1-chloropropyl, 3-chloropropyl, 1-chlorobutyl,1-chloropentyl, 1-chlorohexyl, 4-chlorobutyl and the like. Also, theterm "C₃ -C₈ cycloalkyl" is used to refer to a cycloalkyl radical having3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

When R₁ in formula (I) is --CH₂ CONR₇ R₈ wherein --NR₇ R₈ represents theresidue of a saturated monocyclic secondary amine, such monocyclespreferably have 5 to 7 ring atoms optionally containing another heteroatom (--O--, --S-- or --N--) in addition to the indicated nitrogen atom,and optionally bear one or more substituents such as phenyl, benzyl andmethyl. Illustrative of residues of saturated monocyclic secondaryamines which are encompassed by the --NR₇ R₈ term are morpholino,1-pyrrolidinyl, 4-benzyl-1-piperazinyl, perhydro-1,2,4-oxathiazin-4-yl,1- or 4-piperazinyl, 4-methyl-1-piperazinyl, piperidino,hexamethyleneimino, 4-phenylpiperidino, 2-methyl-1-pyrazolidinyl, 1- or2-pyrazolidinyl, 3-methyl-1-imidazolidinyl, 1-or 3-imidazolidinyl,4-benzylpiperidino and 4-phenyl-1-piperazinyl.

Selected compounds of formula (I), i.e. compounds wherein R₁ isα-haloalkyl, readily form the corresponding soft quaternary ammoniumsalts which are likewise useful as soft anti-inflammatory agents. Thus,for example, the selected haloalkyl derivative of formula (I) can simplybe reacted with a tertiary amine ##STR11## or an unsaturated amine##STR12## to afford the corresponding quaternary ammonium salt. Thereactants are generally used in approximately equimolecular proportionsand the reaction is conducted in the presence of an inert solvent (e.g.,ether, acetonitrile, CH₂ Cl₂ or the like), at a temperature of from roomtemperature to the reflux temperature of the solvent, for approximately2 to 24 hours. Alternatively, the reaction can be conducted in theabsence of a solvent by mixing the two reactants together andmaintaining them at room temperature or between 20° to 70° C. for 2 to24 hours. In either case, the crystalline salt formed can be purified bycrystallization from an ether-ethanol mixture, or the like.

The expression "unsaturated amine" used above denotes N-heterocyclicunsaturated systems having 3 to 10 members in the ring, and substitutedderivatives thereof, where the unsaturation corresponds to the maximumnumber of non-cumulative double bonds, provided that the nitrogen atomcontains no hydrogen atom as a substituent. The following examples willsufficiently illustrate the scope of the defined term: ##STR13##

Substituted derivatives of the unsaturated amines include groups asshown above containing one or more alkyl, --COO(alkyl) or --OCO(alkyl)substituents.

With respect to the expression "tertiary amine", this expression denotesamines wherein the nitrogen atom has no hydrogen atoms attached theretoand which are not among the N-heterocyclic unsaturated systemsencompassed by the expression "unsaturated amine" as defined above.Typically, the term "tertiary amine" includes trialkylamines, whereinthe alkyl groups, which can be the same or different, each preferablycontain 1 to 8 carbon atoms; trialkoxyamines wherein the alkoxy portionseach contain 1 to 8 carbon atoms; tertiary saturated cyclic amines suchas quinuclidine or substituted quinuclidine (e.g.,3-acetoxyquinuclidine); and N-substituted derivatives of secondarysaturated cyclic amines [e.g., an N-substituted derivative ormorpholine, pyrrolidine, imidazolidine, pyrazolidine, piperidine orpiperazine, wherein the N-substituent can be a group such as (C₁ -C₈)alkyl], optionally containing additional substituents such as methyl.

Preferred quaternary ammonium salts include those derived from1,2-dimethylpyrrolidine, 3-acetoxyquinuclidine, 1-methylpyrrolidine,triethylamine and N-methylimidazole. Especially preferred are thequaternary ammonium salts derived from the reaction of the aforesaidamines with compounds of formula (I) wherein Z is β-hydroxymethylene andR₁ is chloromethyl, most especially when R₂ is lower alkyl.

While all of the compounds encompassed by formula (I) above essentiallysatisfy the objectives of the present invention, nevertheless certaingroups of compounds remain preferred. A "first" group of preferredcompounds of formula (I) has been set forth in the Summary of theInvention hereinabove.

Another preferred group of compounds consists of the compounds offormula (I) wherein Z, X, R₁ and R₂ are defined as hereinabove, and theremainder of the structural variations are identical to those ofhydrocortisone (i.e. R₃, R₄ and R₅ are each a hydrogen atom and the1,2-linkage is saturated) or of prednisolone (i.e., R₃, R₄ and R₅ areeach a hydrogne atom and the 1,2-linkage is unsaturated), mostespecially when R₁ and R₂ are as defined with respect to the "first"group of preferred compounds set forth hereinabove.

Another preferred group of compounds consists of the 6α- and/or9α-fluoro and 16α- or 16β-methyl congeners of the compounds indicated inthe preceding paragraph. Within this group, the compounds wherein Z, X,R₁ and R₂ are defined as hereinabove and the remaining structuralvariables are identical to those of fludrocortisone, betamethasone anddexamethasone are particularly preferred, most especially when R₁ and R₂are as defined with respect to the "first" group of preferred compoundsset forth hereinabove. Other compounds of particular interest withinthis group are those wherein Z, X, R₁ and R₂ are defined as hereinaboveand the remaining structural variables are identical to those oftriamcinolone, flumethasone, fluprednisolone or paramethasone,particularly when R₁ and R₂ are as defined with respect to the "first"group of preferred compounds set forth hereinabove. Yet otherinteresting compounds are those wherein Z, X, R₁ and R₂ are defined ashereinabove, R₃ is ##STR14## and the remaining structural variables areidentical to those of triamcinolone, particularly when R₁ and R₂ are asdefined with respect to the "first" group of preferred compounds setforth hereinabove.

In each of the groups of compounds indicated in the three precedingparagraphs, the compounds wherein X is oxygen are particularlypreferred. Most especially preferred are the compounds encompassed bythe groups indicated above wherein Z is β-hydroxymethylene, wherein X isoxygen, wherein R₂ is C₁ -C₆ alkyl (particularly methyl, ethyl, propylor isopropyl), and wherein R₁ is C₁ -C₆ alkyl, C₁ -C₆ (monohalo)alkyl(particularly chloromethyl) or --CH₂ --Y--(C₁ -C₆ alkyl) wherein Y isdefined as hereinabove (particularly when the C₁ -C₆ alkyl group ismethyl).

The compounds of formula (I) can generally be prepared by known methods,the method of choice being dependent on the identity of the varioussubstituents in the desired final product.

One generally useful method for the preparation of the compounds offormula (I) wherein Z is β-hydroxymethylene and X is oxygen utilizessteroidal starting materials of the formula ##STR15## wherein R₄, R₅ andthe dotted line in ring A are defined as before and R₃ ' is hydrogen,α-methyl, β-methyl, α-OH, β-OH or ═CH₂ (and which can be convenientlyprepared by treatment of the corresponding 21-hydroxypregnenolones ofthe formula ##STR16## wherein R₄, R₅, R₃ ' and the dotted line in ring Aare defined as above with NaIO₄ in a suitable organic solvent at room orelevated temperature.) According to this process of the invention, astarting material of formula (II) is reacted with R₂ OCOCl or R₂ OCOBr(formed by reacting R₂ OH with COCl₂ or COBr₂, wherein R₂ is defined asabove), under anhydrous conditions, in an appropriate inert organicsolvent such as dichloromethane, chloroform or tetrahydrofuran,preferably in the presence of a suitable acid acceptor (e.g.,triethylamine, pyridine, calcium carbonate or other appropriate base).Time and temperature are not critical factors; however, the reaction isconveniently carried out at a temperature between 0° C. and roomtemperature, for about 1 to 6 hours. The resultant novel 17β-carboxylicacid 17α-carbonate has the formula ##STR17## wherein R₂, R₄, R₅ and thedotted line in the A ring are defined as above and R₃ " is H, α-CH₃,β-CH₃, α-OCOOR₂, β-OCOOR₂ or ═CH₂. When R₃ ' in the starting material offormula (II) is α-OH or β-OH, sufficient R₂ OCOCl or R₂ OCOBr isgenerally employed to ensure formation of the carbonate grouping at the16-position as well as at the 17-position [i.e., when R₃ ' in formula(II) is OH, R₃ " in the resultant intermediate of formula (III) is α- orβ-OCOOR₂ ].

Sometimes, when a compound of formula (I) wherein R₂ contains a sulfinylor sulfonyl grouping is desired, such a grouping is not introduced viathe R₂ OCOCl/R₂ OCOBr reaction, but is prepared from the correspondingthio-containing R₂ derivative at a later stage in the synthetic scheme,as will be discussed in more detail below.

After the above-described introduction of the 17α-substituent, theresultant novel intermediate of formula (III) is converted to itscorresponding metal salt of the formula ##STR18## wherein R₂, R₃ ", R₄,R₅ and the dotted line in the ring A are defined as above, and M is asuitable metal, e.g. alkali metal (such as sodium or potassium),alkaline earth metal/2, or thallium or NH₄ ⁺. The novel salt of formula(IV) is typically formed by reacting the steroid of formula (III) with ahydroxide (MOH) or alkoxide (MOR) in a appropriate organic solvent, suchas ethyl ether or tetrahydrofuran, at a temperature of 0° C. to roomtemperature, for 0.5 to 4 hours. Then, the salt of formula (IV) isreacted with a compound of the formula R₁ -W wherein R₁ is defined ashereinabove and W is halogen, to afford the desired final product offormula (I). This step of the reaction sequence can be convenientlyconducted at room temperature for about 1 to 24 hours, or at the boilingof the solvent (i.e. acetonitrile, THF, etc.) When it is desired tointroduce a halo-substituted R₁ grouping into the steroid, e.g., when acompound of formula (I) wherein R₁ is chloromethyl is desired, it hasbeen found that the reaction proceeds well using hexamethylphosphoramideas the solvent at lower temperatures (0°-10° C.) and employing a R₁ -Wreactant wherein W is iodine (e.g., iodochloromethane). When anon-halogen containing R₁ grouping is desired (e.g., R₁ =alkyl or --CH₂COOR₆ where R₆ is alkyl, etc.), no such restrictions need by placed onthe R₁ -W reactant or on the solvent; thus, W can be any halogen,preferably chloro or bromo, and the usual organic solvents such asdimethylformamide, dichlormethane, acetonitrile, tetrahydrofuran orchloroform can, if desired, be used instead of hexamethylphosphoramide.When a compound of formula (I) wherein R₁ contains a sulfinyl orsulfonyl grouping is desired, such a grouping is not generallyintroduced via the R₁ -W reaction, but is subsequently prepared from thecorresponding thio steroid, as described below.

The compounds of formula (I) wherein R₁ (or R₂) is a sulfinyl- orsulfonyl-containing grouping can be prepared by oxidation of thecorresponding thio steroids. Thus, for example, a compound of formula(I) wherein R₁ is ##STR19##

[wherein R₉ is H, lower alkyl, or combined with the lower alkyl groupadjacent to S to form a cyclic system, as described hereinabove] can bereacted wtih 1 equivalent of m-chloroperoxybenzoic acid at 0°-25° C. for1 to 24 hours, in a suitable solvent such as chloroform, to afford thecorresponding compound of formula (I) wherein R₁ is ##STR20## or with 2equivalents of m-chloroperoxybenzoic acid to afford the correspondingcompound of formula (I) wherein R₁ is ##STR21## This type of reactioncan also be utililzed to prepare compounds of formula (I) wherein R₁ is--CH₂ COOR₆ wherein R₆ is substituted alkyl, cycloalkyl, cycloalkenyl,alkenyl, phenyl, or benzyl, wherein the substituent is loweralkylsulfinyl or lower alkylsulfonyl, from the corresponding loweralkylthio-substituted formula (I) steroids; to prepare compounds offormula (I) wherein R₁ is lower alkylsulfinyl- oralkylsulfonyl-substituted phenyl or benzyl from the corresponding loweralkylthio-substituted formula (I) steroids; and to prepare compounds offormula (I) wherein R₂ is substituted alkyl, cycloalkyl, cycloalkenyl,alkenyl, phenyl or benzyl wherein the substituent is lower alkylsulfinylor lower alkylsulfonyl, from the corresponding loweralkylthio-substituted formula (I) steroids.

When the compounds of formula (I) wherein R₃ is α- or β-hydroxy aredesired, same can be prepared by partial acid hydrolysis of thecorresponding compounds of formula (I) wherein R₃ is α- or β-OCOOR₂, ina suitable solvent medium. Use of a mild reagent, e.g., oxalic acid inmethanol, is desirable. Alternatively, hydrolysis of the 16-carbonate tothe 16-hydroxy compound could be carried out at an earlier stage in anysynthetic scheme described herein after the introduction of the16,17-carbonate groupings, e.g., selective hydrolysis of an intermediateof formula (III) having 16 and 17 carbonate groupings to thecorresponding 16-hydroxy 17-carbonate, followed by conversion to thecorresponding compound of formula (I) as described supra.

Another process for the preparation of the compounds of formula (I)wherein Z is β-hydroxymethylene and X is oxygen utilizes the same17α-hydroxy-17β-carboxylic acid starting materials of formula (II) asare employed in the synthetic scheme described supra, but involvesformation of the 17β-COOR₁ grouping prior to, rather than after,introduction of the 17α-OCOOR₂ substituent. Essentially, the samenon-steroidal reactants, reaction conditions, etc., as described aboveare used for the introduction of each group. Thus, the starting materialof formula (II) is first reacted with MOH or MOR to form thecorresponding intermediate of the formula ##STR22## wherein R₃ ', R₄, R₅and M and the dotted line in ring A are defined as above, which is thenreacted with R₁ W wherein R₁ and W are defined as above, to afford thecorresponding 17β-carboxylate of the formula ##STR23## wherein R₁, R₃ ',R₄, R₅ and the dotted line in ring A are defined as above, which is inturn reacted with R₂ OCOCl or R₂ OCOBr wherein R₂ is defined as above,to afford the corresponding 17α-carbonate of formula (I). The variousparameters of the process of converting (II) to (V) are the same asthose discussed in detail above with respect to the conversion of (III)to (IV). Likewise, the process parameters for converting (V) to (VI)parallel those detailed above with respect to converting (IV) to (I).Similarly, the process parameters for converting (VI) to (I) arebasically the same as those given above for the conversion of (II) to(III). Thus, again, when the starting material contains a 16-hydroxygroup, the 16,17-dicarbonate of formula (I) will be formed which canthen be selectively hydrolyzed, if desired, to the corresponding16-hydroxy-17-carbonate of formula (I). And, again, the compounds offormula (I) in which R₁ or R₂ is a sulfinyl- or sulfonyl-containinggrouping can be conveniently prepared by oxidation of the correspondingthio-containing compounds of formula (I) as detailed hereinabove.Alternatively, the compounds of formula (I) wherein R₁ is ##STR24## canbe prepared by oxidation, preferably with m-chloroperoxybenzoic acid, ofthe corresponding compounds of formula (VI) in which R₁ is athio-containing group, followed by introduction of the 17α-OCOOR₂substituent to the resultant sulfinyl or sulfonyl compound.

Another possible process for the preparation of the compounds of thepresent invention, which can be used to prepare compounds of formula (I)wherein Z is β-hydroxymethylene and X is oxygen or sulfur, utilizes the17β-carboxylic acid 17α-carbonate intermediates of formula (III) above.According to this process, an intermediate of formula (III) issuccessively treated, first with a mild acyl chloride forming agent,e.g. such as diethylchlorophosphate or oxalyl chloride, to form thecorresponding novel acid chloride of the formula ##STR25## wherein R₂,R₃ ", R₄, R₅ and the dotted line in ring A are defined as above, andthen with R₁ XM' wherein R₁ and X are defined as before, and M' ishydrogen or M (M is defined as above), in an inert solvent (e.g., CHCl₃,THF, acetonitrile or DMF), at a temperature between about 0° C. and theboiling point of the solvent, for 1 to 6 hours, to afford thecorresponding compound of formula (I). When using a compound of theformula R₁ XM' wherein M' is hydrogen, an acid scavenger such astriethylamine is preferably present in the reaction system. The twosteps of this process can be very conveniently run in the same solvent,without isolating the acid chloride of formula (VIII) formed in thefirst step. This process is of particular value when a compound offormula (I) wherein X is S is desired.

Yet another desirable process for the preparation of the compounds offormula (I) wherein Z is β-hydroxymethylene and X is oxygen utilizes the17α-hydroxy-17β-carboxylates of formula (VI) above. According to thisprocess, an intermediate of formula (VI) is reacted with phosgene, in asuitable organic solvent (e.g., toluene, benzene, CH₂ Cl₂ oracetonitrile) at a low temperature (-20° C. to room temperature, e.g.,0° C.), for about 2 hours (or until the reaction is complete).Evaporation to remove solvent and excess phuosgene affords the desirednovel 17α-chlorocarbonyloxy-17β-carboxylate intermediate of the formula##STR26## wherein R₁, R₄, R₅ and the dotted line in ring A are definedas above, R₃ "' is hdyrogen, α-methyl, β-methyl, α-OCOCl, β-OCOCl or═CH₂. When R₃ ' in the starting material of formula (VI) is hydroxy,sufficient phosgene is generally employed to ensure formation of thechlorocarbonyloxy grouping at the 16-position as well as the 17-position[i.e., when R₃ ' in formula (VI) is α-OH or β-OH, R₃ "' in the resultantintermediate of formula (VII) is α- or β-OCOCl]. The intermediate offormula (VII) is then reacted with a compound of the formula R₂ OM'wherein R₂ and M' are defined as above, in an inert solvent, preferablyin the presence of an acid scavenger (e.g. triethylamine), to afford thecorresponding compound of formula (I). When R₂ OM' is an alcohol of theformula R₂ OH, the reaction is conducted under the same conditions as inthe reaction for conversion of compound (II) to compound (III). On theother hand, if a compound of the formula R₂ OM is employed as R₂ OM',the reaction conditions are described as above for conversion ofcompound (VIII) to compound (I). When R₃ "' in th formula (VII) isOCOCl, sufficient R₂ OM' is generally utilized to ensure conversion ofboth the 16- and 17α-substituents to OCOOR₂ groupings in the finalproduct. And, again, the 16-hydroxy and the sulfinyl- and sulfonyl-containing compounds of formula (I) are most conveniently formed as afinal step in the synthetic scheme.

As a variation of the process described immediately above, a steroidal17α-hydroxy-17β-carboxylic acid starting material of formula (II) can bereacted with phosgene as described above, to afford the17α-chlorocarbonyloxy-17β-carboxylic acid intermediate of the formula##STR27## wherein R₃ "', R₄, R₅ and the dotted line in ring A aredefined as above, which can then be reacted with R₂ OM' as describedsupra, to afford the corresponding compound of formula, (III) above. Thenovel intermediate can then be converted to a corresponding compound offormula (I) as described supra. Once again, the 16-hydroxy and thesulfinyl and sulfonyl derivatives are best prepared as a final step.

Still another process for the preparation of the compounds of formula(I) wherein Z is β-hydroxymethylene and X is oxygen utilizes the17α-hydroxy-17β-carboxylates of formula (VI) above. In accord with thismethod, an intermediate of formula (VI) is reacted with an excess amountof a carbonate of the formula ##STR28## (which can be convenientlyprepared by reacting phosgene with 2 equivalents of R₂ OH) in thepresence of an acid catalyst, to afford the corresponding compound offormula (I). Depending on the nature of the R₂ grouping, the ##STR29##reactant can also act as the solvent at the boiling point of thecarbonate reactant, or at the boiling point of the corresponding R₂ OH(which can conveniently be removed in this way from the reactionmixture, driving the reaction to completion), or the reactants can becombined in an appropriate inert organic solvent (e.g., an aromatic suchas benzene or toluene, or a halogenated hydrocarbon such asdichloromethane or chloroform). And, again, the 16-hydroxy and thesulfinyl and sulfonyl compounds of formula (I) can conveniently beprepared as a final step in the process, although the intermediate offormula (VI) in which R₁ contains a sulfur atom could be first oxidized,and the resultant sulfinyl or sulfonyl compound of formula (VI) thenreacted with ##STR30##

Other procedures for the preparation of selected compounds of formula(I) will be apparent to those skilled in the art. By way of example, acompound of formula (I) wherein R₁ or R₂ is halo-substituted can besubjected to a halogen exchange reaction in order to replace the halogenwith a different halogen according to the order of reactivity Cl<Br<I.For example, reacting a chloroalkyl 17β-carboxylate of formula (I) withan alkali metal iodide, e.g., sodium iodide, will afford thecorresponding iodoalkyl 17β-carboxylate. Similarly, a bromide salt(e.g., lithium bromide) can be reacted with a chloroalkyl17β-carboxylate to give the corresponding bromoalkyl 17β-carboxylate. Asuitable solvent for either reaction may be selected from the groupconsisting of hexamethylphosphoramide, acetone, ethanol, methyl ethylketone, dimethylacetamide, dimethylformamide and acetonitrile.

In like manner, a halogen exchange reaction based on relativesolubilities can be used to convert a chloroalkyl 17β-carboxylate or aniodoalkyl 17β-carboxylate of formula (I) to the correspondingfluoroalkyl derivative. Silver fluoride can be employed in thisreaction, which is conducted in a suitable organic solvent (e.g.,aceytonitrile), and which is especially useful in the preparation of thecompounds in which R₁ is fluoromethyl or fluoroethyl.

The 21-hydroxypregnenolones from which the steroidal starting materialsof formula (II) are prepared can be obtained commercially or prepared byknown methods. Likewise, the non-steroidal starting materials used inthe various processes discussed above are commercially available or canbe prepared by known chemical procedures.

Also, a starting material of formula (II) above can be reacted with acompound of the formula R₂ OCOCl or R₂ OCOBr wherein R₂ is as definedabove, to afford an intermediate of the formula ##STR31## wherein R₂, R₃", R₄, R₅ and the dotted line in ring A are defined as above, which canbe converted to the corresponding intermediate of formula (III) above bypartial hydrolysis, with or without isolation of the compound of formula(XI). This reaction of a starting material of formula (II) with R₂ OCOClor R₂ OCOBr can be carried out under the same conditions as the reactionof a compound of formula (II) with R₂ OCOCl or R₂ OCOBr as describedhereinabove, except that R₂ OCOCl or R₂ OCOBr is used in an amount of 2moles or more to one mole of the compound of the formula (II). Thepartial hydrolysis of the resultant compound of the formula (XI) can becarried out in an inert solvent in the presence of a catalyst. Examplesof suitable catalysts include tertiary alkyl amines such astriethylamine, trimethylamine or the like; aromatic amines such aspyridine, 4,4-dimethylaminopyridine, quinoline or the like; secondaryalkyl amines such as diethylamine, dimethylamine or the like; andinorganic bases such as sodium hydroxide, potassium hydroxide, potassiumbicarbonate, or the like. Preferably, pyridine and potassium bicarbonateare employed. Examples of suitable inert solvents for use in thehydrolysis include water; lower alcohols such as ethanol, methanol orthe like; ethers suchy as dimethyl ether, diethyl ether,dimethoxyethane, dioxane, tetrahydrofuran, or the like; halogenatedhydrocarbons such as dichloromethane, chloroform or the like; tertiaryamines such as pyridine, triethylamine or the like; or a mixture of twoor more of the solvents mentioned above. The reaction is usually carriedout a temperature of from about 0° to 100° C., preferably at roomtemperature to 50° C., for 1 to 48 hours, preferably for 2 to 5 hours.

In yet another aspect, the present invention provides novel compounds ofthe formula ##STR32## wherein R₁, R₂, R₃, R₄, R₅, X and the dotted linein ring A are as defined with respect to formula (I) above. The 11-ketocompounds of formula (IX) can be prepared by the procedures describedhereinabove for the preparation of the corresponding 11β-hydroxycompounds of formula (I). Thus, a starting material corresponding toformula (II) but having an 11-keto group is reacted with R₂ OCOCl or R₂OCOBr, to afford the corresponding novel intermediate corresponding toformula (III) but having an 11-keto group; that intermediate is thenconverted to its metal salt, which corresponds to formula (IV) exceptfor the presence of an 11-keto instead of an 11β-hydroxy group; and themetal salt is then reacted with R₁ W to afford the correspondingcompound of formula (IX). All reaction conditions are as previouslydescribed with respect to the corresponding processes for preparing thecorresponding compounds of formula (I). Also, the preparation of thecompounds of formula (IX) wherein R₁ is a sulfinyl- or sulfonyl-containing grouping or wherein R₃ is hydroxy generally proceeds as afinal step in the synthetic scheme in a manner analogous to that usedfor the corresponding compounds of formula (I). Further, all of theabove-described alternative processes for the preparation of thecompounds of formula (I) are equally applicable to the preparation ofthe compounds of formula (IX) by simply substituting the 11-oxo startingmaterial for the corresponding 11β-hydroxy steroids used therein, e.g.,replacing the 11-hydroxy group in formulas (V), (VI), (VII), (VIII), (X)and (XI) with an 11-oxo group and otherewise proceeding as describedhereinabove for the reactions (II)→(V)→(VI)→(I); (III)→(VIII)→(I);(VI)→(VII)→(I); (II)→(X)→(I); (VI)→(I), etc.

Also, the compounds of formula (IX) can be prepared by reacting thecorresponding compounds of formula (I) with an oxidizing agent. Theoxidation of a compound of formula (I) in order to convert it into thecorresponding compound of formula (IX) is usually carried out by usingan oxidizing agent in an appropriate solvent. The solvent may be anyconventional solvent, for example, water, and organic acid (e.g. formicacid, acetic acid, trifluoroacetic acid), an alcohol (e.g. methanol,ethanol), a halogenated hydrocarbon (e.g. chloroform, dichloromethane),or the like. This oxidizing agent may also be any conventional agentwhich is effective for oxidizing a hydroxy group to a carbonyl group,for example, pyridinium chlorochromate, chromium trioxide in pyridine,hydrogen peroxide, dichromic acid, dichromates (e.g. sodium dichromate,potassium dichromate), permanganic acid, permanganates (e.g. sodiumpermanganate, potassium permanganate), or the like. The oxidizing agentis usually used in an amount of 1 mole or more, preferably 1 to 3 mole,per mole of the compound of formula (I). The reaction is usually carriedout at a temperature of 0° to 40° C., preferably at around roomtemperature, for about 6 to 30 hours.

The novel compounds of formula (IX) are useful as soft steroidalanti-inflammatory agents and also in vivo or in vitro precursors of thecorresponding 11β-hydroxy compounds. Thus, the compounds of formula (IX)can be reduced in vitro to afford the corresponding compounds of formula(I), using a reducing agent known to be capable of reducing the 11-oxogroup to an a 11β-hydroxy group without modifying the remainder of thesteroidal starting material. Typically, microbiological reduction isadvantageous for carrying out the desired conversion, although chemicalreduction also is possible. Further, the compounds of formula (IX) maybe formulated into appropriate dosage forms (e.g., retention enemas) forthe treatment of conditions such as ulcerative colitis. In such dosageforms, it is thought that the compounds of formula (IX) aremicrobiologically reduced by bacteria in the body (e.g. in the colon) tothe highly active 11β-hydroxy steroids, which elicit the desiredanti-inflammatory response.

The preferred compounds of formula (IX) are those which are precursorsof the preferred compounds of formula (I) wherein Z isβ-hydroxymethylene, namely corresponding 11-keto compounds of formula(IX). As especially preferred group of compounds of formula (IX)consists of those wherein X, R₁ and R₂ are defined as above with respectto formula (I) and the remaining structural variations are identical tothose of cortisone (i.e. R₃, R₄ and R₅ are each a hydrogen atom and the1,2-linkage is saturated), of prednisone (i.e. R₃, R₄ and R₅ are eachhydrogen and the 1,2-linkage is unsaturated), or of the 6α- and/or9α-fluoro and the 16α- or 16β-methyl congeners thereof, particularlywhen R₁ and R₂ are as defined with respect to the "first" group ofpreferred compounds set forth hereinabove. Most especially preferred ofthese derivatives are those wherein X is oxygen, R₂ is C₁ -C₆ alkyl andR₁ is C.sub. 1 -C₆ alkyl, C₁ -C₆ (monohalo)alkyl [particularlychloromethyl] or --CH₂ --Y--(C₁ -C₆ alkyl) [particularly --CH₂ --Y--CH₃].

The results of various activity studies of representative species of theinvention, discussed in detail below, clearly indicate the potentanti-inflammatory activity and the minimal systemic activity/toxicity ofthe soft steroids of formula (I). In view of this desirable separationof local and systemic activities, the compounds of the invention can beused in the treatment of topical or other localized inflammatoryconditions without causing the serious systemic side effects typicallyexhibited by the known natural and synthetic glucocorticosteroids suchas cortisone, hydrocortisone, hydrocortisone 17α-butyrate, betamethasone17-valerate, triamcinolone, betamethasone dipropionate and the like.

THYMUS INVOLUTION TEST

The test animals were female Sprague/Dawley rats weighing approximately40-45 grams each. One side of each ear of each rat was treated with atotal of 25 microliters of a solution (ethanol/isopropyl myristate oracetone/isopropyl myristate, 90/10) containing the amount of testcompound indicated below. Animals which were treated identically, savefor omission of the test compound, served as controls. After 24 hours,all rats were sacrificed and weighed, and their thymi were removed andweighed. The results are tabulated in Table I below, the weights of thethymi being expressed as mg/100 g of rat.

                                      TABLE I                                     __________________________________________________________________________    Effect of topically administered soft steroids and reference steroids on      thymus                                                                        weight in rats.                                                                         Amount                                                                        of                   Total Weight                                             Test                 per Rat (g)                                              Compound                                                                            Number                 %                                      Test Compound                                                                           Applied (μmol)                                                                   of  Rats                                                                            ##STR33##                                                                               Starting                                                                           Final                                                                           Gain ± SD                           __________________________________________________________________________    None (Control)                                                                          --    8    364 ± 29                                                                             48.44                                                                              61.42                                                                            27 ± 6                              Hydrocortisone                                                                          0.75  8    274 ± 45                                                                             49.44                                                                              61.15                                                                            24 ± 7                              Chloromethyl                                                                            0.75  8    347 ± 31                                                                             48.06                                                                              62.10                                                                            29 ± 5                              11β-hydroxy-17α-                                                   methoxycarbonyl-                                                              oxyandrost-4-en-                                                              3-one-17β-carboxy-                                                       late                                                                          Chloromethyl                                                                            0.75  7    309 ± 24                                                                             45.57                                                                              60.60                                                                            33 ± 6                              17α-ethoxycar-                                                          bonyloxy-11β-                                                            hydroxyandrost-                                                               4-en-3-one-17β-                                                          carboxylate                                                                   __________________________________________________________________________

The change in weight in the thymi is a measure of systemic activity andhence of toxicity. The lower the weight of the thymi, the greater thesystemic activity. As can be seen from the above data, evenhydrocortisone, the natural glucocorticoid, causes a significantdecrease in thymus weight compared to the control. The decreases causedby equal doses of representative species of the invention are much lesssignificant, indicating those compounds have much less systemic activitythan hydrocortisone.

BLANCHING STUDIES

MeKenzie-type human blanching studies were undertaken to study theblanching effects of a representative test compound of the invention,chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate. Theability of a compound to cause blanching in humans has been found tocorrelate closely with its anti-inflammatory activity.

The test compound was dissolved in ethanol/isopropyl myristate (90/10 or70/30) at 0.03, 0.01, 0.003, 0.001 and 0.0003M concentrations. 50Microliter aliquots of each solution were applied to separate gauzeportions of a bandage of the type commonly used for allergy testing andthe bandage was applied to the forearm. After 6 hours of occlusion, thebandage was removed. After 1 to 5 hours after removal of the bandage,blanching was observed even at the lowest concentrations of testcompound.

When hydrocortisone was tested according to the above procedurecomparing it directly to the test compound, blanching was not observedat concentrations of hydrocortisone below 0.03M. Further, it was notedthat 0.03M hydrocortisone caused approximately the same degree ofblanching as that resulting from use of 0.001M chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate.

EAR EDEMA TEST

The test animals were Sprague/Dawley rats weighing approximately 150grams each. In treatment groups, selected amounts of the test compoundwere dissolved in acetone containing 5% croton oil and 50 microliters ofthe solution were applied to the inner surface of the right ear of therats. A control group was identically treated with vehicle only, i.e. 5%croton oil in acetone. Six hours after croton oil challenge, a constantregion of each ear was removed by dissection under anesthesia. Then, 48hours after steroid treatment, the animals were sacrificed and the thymiand adrenals were removed and weighed. The test results showing theinhibitory effect of topically applied steroids on the ear swellinginduced by croton oil are summarized in Table II below.

                                      TABLE II                                    __________________________________________________________________________    Effect of topically applied soft steroid and reference steroids on ear        swelling                                                                      induced by croton oil.                                                                                                          Relative Organ                             Number                                                                             Ear Weight (mg).sup.b         Weight                      Test      Dose.sup.a                                                                         of Test                                                                            Inflamed                                                                              Untreated             (mg/100 g body wt.)         Compound  mg/kg                                                                              Animals                                                                            Ear     Ear   % Increase                                                                             % Inhibition                                                                         Thymus Adrenals             __________________________________________________________________________    None (Control) 5    75.2 ± 4.5                                                                         46.6 ± 1.4                                                                       61.4 ± 8.9   333 ± 15                                                                          23.3 ± 1.7        Chloromethyl 17α-                                                                 0.3  5    62.2 ± 3.0*                                                                        50.8 ± 2.4                                                                       23.3 ± 7.2*                                                                         62.1   290 ± 25                                                                          26.0 ± 2.5        ethoxycarbonyloxy-                                                            11β-hydroxyandrost-                                                                1    5    55.0 ± 2.6**                                                                       48.4 ± 1.0                                                                       14.0 ± 6.5**                                                                        77.2   293 ± 21                                                                          18.7 ± 1.4        4-en-3-one-17β-                                                          carboxylate                                                                             3    5    52.6 ± 1.8**                                                                       51.6 ± 3.2                                                                        3.7 ± 8.1**                                                                        94.0   288 ± 21                                                                          20.3 ± 0.8        Hydrocortisone                                                                          1    5    50.0 ± 2.3**                                                                       52.0 ± 2.5                                                                       -3.6 ± 3.5**                                                                        106.0  303 ± 21                                                                          20.2 ± 0.7        17-butyrate                                                                   Betamethasone                                                                           1    5    55.4 ± 1.2*                                                                        50.4 ± 2.0                                                                       10.9 ± 6.3**                                                                        82.2    267 ± 19*                                                                        18.9 ± 1.9        17-valerate                                                                   __________________________________________________________________________     .sup.a calculated values based on application of 50 μl of steroid          solution.                                                                     .sup.b 50 μl of 5% croton oil/acetone and drugs in 5% croton               oil/acetone were applied to the right ear. Ear weight was measured 6 hr       after topical application.                                                    *p < 0.05; **p < 0.01: Significant difference from control.              

As can be seen from Table II above, the representative species of thepresent invention, namely chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,substantially inhibited the swelling (and consequent increased weight)of the ear caused by the croton oil, i.e., the compound exhibitedsubstantial anti-inflammatory activity. On the other hand, in contrastto the effect caused by betametasone 17-valerate, the representativecompound of the invention did not significantly decrease the thymusweight as compared to the control, i.e., it did not show a significantdegree of systemic activity.

GRANULOMA FORMATION TEST

The test compound was dissolved in acetone and aliquots of varyingconcentrations were injected into cotton pellets. The pellets were driedand then one pellet was implanted beneath the skin of each test rat. Sixdays later, the animals were sacrificed and the granulation tissue(granuloma) which formed in and around the implanted pellet was removed,dried and weighed. In addition, the thymi and adrenals were removed andweighed. The ability of a compound to inhibit granuloma formulation inthis test is a direct indication of local anti-inflammatory activity;thus, the lower the weight of granulation tissue, the better theanti-inflammatory activity. On the other hand, a significant decrease inthymus weight is indicative of significant systemic activity;conversely, when a test compound does not significantly decrease thymusweight as compared to the control, such is indicative of a lack of (orvery minimal) systemic side effects.

The results are tabulated in Tables III, IV and V-a and V-b below.

                                      TABLE III                                   __________________________________________________________________________    Effect of locally administered soft steroids and reference steroids on        body weight, thymus weight and                                                granulation tissue formation caused by implantation of cotton pellets in      rats.                                                                                                      Granulation tissue                                                                        Relative                                          Dose                                                                              Number      Dry wt.     organ weight mg/100 g                Test         (mg/                                                                              of Test                                                                            Body wt.                                                                             (mg/100 g                                                                            Inhibition                                                                         body wt. (Decrease %)                Compound     pellet)                                                                           Animals                                                                            gain (g)                                                                             body wt.)                                                                            (%)  Thymus                                                                              Adrenals                       __________________________________________________________________________    None (Control)   10   40.5 ± 0.8                                                                        43.7 ± 4.2                                                                             326 ± 22                                                                         23.7 ± 1.1                  Chloromethyl 17α-                                                                    0.1 8    36.0 ± 2.8                                                                        34.7 ± 4.3                                                                        20.6 282 ± 13                                                                         22.9 ± 2.6                  ethoxycarbonyloxy-                       (13.5)                                                                              (3.4)                          11β-hydroxyandrost-4-en-                                                              0.3 8    33.0 ± 1.3***                                                                     25.3 ± 2.3**                                                                      42.1 298 ± 16                                                                         22.8 ± 1.0                  3-one-17β-carboxylate               (8.6) (3.8)                                       1   8    32.8 ± 0.9***                                                                     14.0 ± 1.8***                                                                     68.0 304 ± 10                                                                         21.8 ± 1.3                                                           (6.7) (8.0)                                       3   7    30.7 ± 1.5***                                                                     18.7 ± 2.3***                                                                     57.2 278 ± 21                                                                         19.6 ± 1.1*                                                          (14.7)                                                                              (17.3)                         Chloromethyl 11β-                                                                     1   7    33.4 ± 1.3***                                                                     24.6 ± 2.6**                                                                      43.7 218 ± 15**                                                                       19.1 ± 1.1**                hydroxy-17α-methoxy-               (33.1)                                                                              (19.4)                         carbonyloxyandrost-4-                                                         en-3-one-17β-carboxylate                                                 Hydrocortisone                                                                             1   8    33.4 ± 1.4***                                                                     32.2 ± 5.0                                                                        26.3  73 ± 5***                                                                       27.1 ± 1.4                  17-butyrate                              (77.6)                                                                              (-14.3)                                     3   8    15.9 ± 1.4***                                                                     21.6 ± 2.2**                                                                      50.6  47 ± 3***                                                                       16.5 ± 1.2***                                                        (85.6)                                                                              (30.4)                                      10  8     4.9 ± 1.0***                                                                     29.2 ± 3.1*                                                                       33.2  32 ± 3***                                                                       16.8 ± 1.2***                                                        (90.2)                                                                              (29.1)                         Betamethasone                                                                              1   8    16.6 ± 1.9***                                                                     35.4 ± 7.3                                                                        19.0  47 ± 2***                                                                       15.5 ± 1.3***               17-valerate                              (85.6)                                                                              (34.6)                                      3   8    14.9 ± 1.7***                                                                     31.6 ± 2.1*                                                                       27.7  38 ± 3***                                                                       13.6 ± 0.9***                                                        (88.3)                                                                              (42.6)                                      10  8    17.0 ± 2.1***                                                                     40.7 ± 2.6                                                                        6.9   43 ± 4***                                                                       12.6 ± 0.9***                                                        (86.8)                                                                              (46.8)                         __________________________________________________________________________     *p < 0.05, **p < 0.01, ***p < 0.001. (mean ± S.E.)     T2 TABLE            IV-Effect of locally administered soft steroids and reference steroids on     body weight, thymus weight and? -granulation tissue formation caused by     implantation of cotton pellets in rats.? -Granulation tissue -? Dose     Number of Body wt. Wet wt. Inhibition -Test Compound (μg pellet) Test     Animals gain (g) (mg) (%)? -None (Control) ? 10 ?  32.4 ± 1.4 566 ±     28  -Chloromethyl 11β-hydroxy- 100 8  34.9 ± 2.7 485 ± 36 14.3     -17α-isopropoxycarbonyloxy- 300 8  33.9 ± 1.6 431 ± 20** 23.9     -androst-4-en-3-one-17β- 1000 8  34.0 ± 2.6 305 ± 16*** 46.1     -carboxylate 3000 8  32.4 ± 2.3 292 ± 7*** 48.4 -Chloromethyl     11β-hydroxy- 30 8  32.4 ± 1.2 432 ± 15** 23.7     -17α-isopropoxycarbonyloxy- 100 7  35.0 ± 1.5 417 ± 27** 26.3     -androsta-1,4-dien-3-one- 300 8  34.4 ± 1.1 369 ± 18*** 34.8     -17β-carboxylate 1000 8  29.4 ± 1.5 289 ± 12*** 48.9     -Chloromethyl 17α-ethoxy- 0.3 8  32.4 ± 1.1 472 ± 23* 16.6     -carbonyloxy-9α-fluoro-11β- 1 8  37.3 ± 1.5* 388 ± 31***     31.4 -hydroxy-16α-methylandrosta- 3 8  34.3 ± 1.1 331 ± 11***     41.5 -1,4-dien-3-one-17β-carboxylate 10 8  36.1 ± 1.1 313 ±     13*** 44.7 - 30 8  31.3 ± 1.4 290 ± 10 48.8 -Chloromethyl     9α-fluoro-11β- 1 7  33.0 ± 1.7 423 ± 19** 25.3     -hydroxy-17α-isopropoxy- 3 8  30.4 ± 1.1 351 ± 19*** 38.0     -carbonyloxy-16β-methylandrosta- 10 8  33.0 ± 1.5 362 ± 8***     36.0 -1,4-dien-3-one-17β-carboxylate 30 8  31.8 ± 1.7 315 ±     12*** 44.3 -Hydrocortisone 300 6  26.2 ± 1.7* 333 ± 21*** 41.2     -17-butyrate 1000 6  26.2 ± 1.2** 366 ± 24*** 35.3 - 3000 6  6.7     ± 2.2*** 329 ± 14*** 41.9 - 10000 6 -2.0 ± 2.4*** 311 ± 7***     45.1 -Betamethasone 100 7  24.9 ± 1.9** 400 ± 19*** 29.3     -17-valerate 300 8  22.3 ± 1.2*** 347 ± 15*** 38.7 - 1000 7  5.3     ± 1.0*** 363 ± 28*** 35.9 - 3000 8  6.6 ± 1.4*** 374 ± 15***     33.9? -Granulation tissue ? -? Dry wt. Inhibition Thymus wt. -Test     Compound (mg) (%) mg (Decrease %)? -None (Control) 81.2 ± 6.3  445 ±     20 -Chloromethyl 11β-hydroxy- 70.0 ± 6.0 13.8 452 ± 29     -17α-isopropoxycarbonyloxy- 50.9 ± 2.8** 37.3 469 ± 25     -androst-4-en-3-one-17β-24.1 ± 2.7*** 70.3 464 ± 30     -carboxylate 20.3 ± 1.3*** 75.0 459 ± 24 -Chloromethyl     11β-hydroxy- 51.0 ± 2.8** 37.2 523 ± 26*     -17α-isopropoxycarbonyloxy- 41.1 ± 5.8*** 49.4 537 ± 31*     -androsta-1,4-dien-3-one- 38.1 ± 5.9*** 53.1 525 ± 28*     -17β-carboxylate 18.5 ± 2.4*** 77.2 423 ± 26 -Chloromethyl     17α-ethoxy- 57.3 ± 5.0* 29.4 492 ± 26     -carbonyloxy-9α-fluoro-11β- 36.4 ± 2.4*** 55.2 519 ± 22*     -hydroxy-16α-methylandrosta- 27.4 ± 2.9*** 66.3 472 ± 16     -1,4-dien-3-one-17β- 22.1 ± 3.6*** 72.8 521 ± 35 -carboxylate     20.4 ± 2.4*** 74.9 505 ± 26 -Chloromethyl 9α -fluoro-11β-     44.4 ± 5.4*** 45.3 526 ± 30* -hydroxy-17α-isopropoxy- 26.9     ± 4.4*** 66.9 471 ± 20 -carbonyloxy-16β-methyl-29.9 ± 3.3***     63.2 474 ± 25 -androsta-1,4-dien-3-one- 19.9 ± 2.3*** 75.5 489 ±     26 -17β-carboxylate -Hydrocortisone 34.0 ± 5.3*** 58.1 353 ±     37* (20.7) -17-butyrate 35.3 ± 4.2*** 56.5  99 ± 7*** (77.8) - 28.0     ± 2.7*** 65.5  58 ± 5*** (87.0) - 27.2 ± 2.4*** 66.5 46 ± 7***     (89.7) -Betamethasone 41.1 ± 2.7*** 49.4 364 ± 24* (18.2)     -17-valerate 33.3 ± 3.6*** 59.0 264 ± 29*** (40.7) - 38.1 ±     4.8*** 53.1  77 ± 5*** (82.7) - 43.0 ± 4.1*** 47.0  63 ± 3***     (85.8)? -

                                      TABLE V-a                                   __________________________________________________________________________    Effect of locally administered soft steroids and reference steroids on        body weight, thymus weight                                                    and granulation tissue formation caused by implantation of cotton pellets     in rats.                                                                      __________________________________________________________________________                                       Granulation Tissue                                        Dose  Number of                                                                            Body wt.                                                                             Wet wt.                                                                              Inhibition                          Test Compound  (μg/pellet)                                                                      Test Animals                                                                         gain (g)                                                                             (mg)   (%)                                 __________________________________________________________________________    None (Control)       10     33.5 ± 1.0                                                                        525 ± 19                                Chloromethyl 17α-ethoxy-                                                               0.3   8      32.5 ± 1.1                                                                        499 ± 36                                                                          5.0                                 carbonyloxy-9α-fluoro-                                                                 1     8      36.3 ± 0.9                                                                        437 ± 24*                                                                         16.8                                11β-hydroxy-16β-methyl-                                                            3     8      33.8 ± 1.3                                                                        422 ± 32*                                                                         19.6                                androsta-1,4-dien-3-one-                                                                     10    8      31.1 ± 1.7                                                                        370 ± 21***                                                                       29.5                                17β-carboxylate                                                          Chloromethyl 9α-fluoro-11β-                                                       0.3   8      35.6 ± 1.0                                                                        454 ± 27*                                                                         13.5                                hydroxy-16α-methyl-17α-                                                          1     8      31.9 ± 0.8                                                                        415 ± 30**                                                                        21.0                                propoxycarbonyloxyandrosta-                                                                  3     7      34.1 ± 1.9                                                                        360 ± 18***                                                                       31.4                                1,4-dien-3-one-17β-                                                                     10    8      33.1 ± 1.6                                                                        350 ± 13***                                                                       33.3                                carboxylate                                                                   Betamethasone  10    6      31.8 ± 1.6                                                                        375 ± 19***                                                                       28.6                                17-valerate    30    6      30.8 ± 3.0                                                                        412 ± 42*                                                                         21.5                                               100   6      25.7 ± 1.2***                                                                     419 ± 20**                                                                        20.2                                Clobetasol     1     8      33.0 ± 1.2                                                                        401 ± 29**                                                                        23.6                                17-propionate  3     7      24.9 ± 1.8***                                                                     402 ± 40**                                                                        23.4                                               10    8      25.0 ± 2.1**                                                                      364 ± 25***                                                                       30.7                                               30    8      24.8 ± 1.1***                                                                     320 ± 10***                                                                       39.0                                               100   8      15.9 ± 1.0***                                                                     325 ± 12***                                                                       38.1                                __________________________________________________________________________                         Granulation Tissue                                                            Dry wt.                                                                              Inhibition                                                                         Thymus wt.                                   Test Compound        (mg)   (%)  mg     (Decrease %)                          __________________________________________________________________________    None (Control)       80.1 ± 5.1                                                                             495 ± 36                                  Chloromethyl 17α-ethoxy-                                                                     61.8 ± 5.7*                                                                       22.8 501 ± 29                                  carbonyloxy-9α-fluoro-                                                                       57.0 ± 6.2*                                                                       28.8 566 ± 31                                  11β-hydroxy-16β-methyl-                                                                  47.5 ± 5.0***                                                                     40.7 500 ± 27                                  androsta-1,4-dien-3-one-                                                                           34.8 ± 5.5***                                                                     56.6 421 ± 30                                  17β-carboxylate                                                          Chloromethyl 9α-fluoro-11β-                                                             55.1 ± 6.2**                                                                      31.2 523 ± 28                                  hydroxy-16α-methyl-17α-                                                                42.9 ± 5.1***                                                                     46.4 453 ± 21                                  propoxycarbonyloxyandrosta-                                                                        29.7 ± 3.2***                                                                     62.9 504 ± 42                                  1,4-dien-3-one-17β-                                                                           28.5 ± 2.8***                                                                     64.4 547 ± 26                                  carboxylate                                                                   Betamethasone        38.5 ± 6.2***                                                                     51.9 479 ± 25                                                                          (3.2)                                 17-valerate          46.2 ± 7.4**                                                                      42.3 484 ± 23                                                                          (2.2)                                                      41.0 ± 4.2***                                                                     48.8 378 ± 30*                                                                         (23.6)                                Clobetasol           42.0 ± 5.8***                                                                     47.6 478 ± 22                                                                          (3.4)                                 17-propionate        43.1 ± 8.9**                                                                      46.2 449 ± 21                                                                          (9.3)                                                      37.9 ± 6.8***                                                                     52.7 322 ± 22**                                                                        (34.9)                                                     25.5 ± 2.1***                                                                     68.2 174 ± 26***                                                                       (64.8)                                                     23.9 ± 3.3***                                                                     70.2  84 ± 3***                                                                        (83.0)                                __________________________________________________________________________     *p < 0.05, **p < 0.01, ***p < 0.001. (Mean ± S.E.)                    

                                      TABLE V-b                                   __________________________________________________________________________    Effect of locally administered soft steroids on body weight, thymus           weight and                                                                    granulation tissue formation caused by implantation of cotton pellets in      rats.                                                                                             Number      Dry granulation Tissue                                      Dose  of Test                                                                            Body wt.      Inhibition                                                                         Thymus wt.                        Test Compound (μg/pellet)                                                                      animals                                                                            gain (g)                                                                             mg     %    mg                                __________________________________________________________________________    None (Control)                                                                              --    10   28.0 ± 1.5                                                                        67.2 ± 3.4                                                                             505 ± 22                       Chloromethyl 9α-fluoro-17α-                                                      1    8    28.9 ± 1.1                                                                        59.1 ± 5.8                                                                        12.1 441 ± 24                       isopropoxycarbonyloxy-16β-                                                              3    8    25.8 ± 0.9                                                                        49.4 ± 37**                                                                       26.5 519 ± 31                       methylandrosta-1,4-dien-                                                                    10    7    28.4 ± 0.8                                                                        51.1 ± 5.8*                                                                       24.0 547 ± 35                       3,11-dione-17β-carboxylate                                                             30    8    27.4 ± 0.9                                                                        40.6 ± 3.6***                                                                     39.6 536 ± 24                       Chloromethyl 17α-ethoxy-                                                               1    7    23.7 ± 1.5                                                                        55.3 ± 2.6*                                                                       17.7 459 ± 41                       carbonyloxy-9α-fluoro-16α-                                                       3    8    25.6 ± 1.2                                                                        51.6 ± 5.9*                                                                       23.2 467 ±  21                      methylandrosta-1,4-dien-                                                                    10    8    26.5 ± 2.5                                                                        41.5 ± 4.7***                                                                     38.2 544 ± 31                       3,11-dione-17β-carboxylate                                                             30    8    20.3 ± 0.9**                                                                      39.9 ± 3.6***                                                                     40.6 463 ± 24                       __________________________________________________________________________     *p 0.05, **p 0.01, ***p 0.001. (Mean ± S.E.)                               Male SpragueDawley rats, weighing 152-189 g (mean body weight 171 g), wer     used. Cotton pellet weight was 30.1 + 0.3 mg (number of test animals were     30).                                                                     

The test data in Tables III, IV and V-a and V-b above clearly show thatthe representative compounds of the present invention exhibited asignificant anti-inflammatory response at lower dosages than did theprior art steroids, hydrocortisone 17-butyrate and betamethasone17-valerate. On the other hand, all of the prior art steroidsdramatically decreased the weight of the thymi and thus showed verypotent systemic activity, while the representative compounds of theinvention either did not significantly decrease the thymi weights oronly minimally decreased the thymi weight. Thus, the present compoundshave a much greater therapeutic index, i.e., separation of localanti-inflammatory from systemic activity, than do the prior artsteroidal anti-inflammatory agents.

Also the test data in Table V-b above shows that the representativecompounds of the present invention exhibited a significant localanti-inflammatory activity.

From the results tabulated in Tables IV and V-b, the ED₄₀ 's, ED₅₀ 'sand ED₆₀ 's and the relative potencies of representative compounds ofthe invention were calculated and are shown in Table VI below. One ofthe compounds of the invention, namely chloromethyl11-hydroxy-17-isopropoxycarbonyloxyandrost-4-en-3-one-17-carboxylate,has been asigned a potency value of 1 at each ED level, and thepotencies of the other compounds are expressed relative thereto. TheED₄₀ 's, ED₅₀ 's and ED₆₀ 's are the dosages required to achieve,respectively, 40%, 50% and 60% reduction in the weight of thegranulation tissue.

                                      TABLE VI                                    __________________________________________________________________________    Relative potencies of soft steroids in the local cotton pellet granuloma      assay.                                                                                           ED.sub.40 .sup.1                                                                     Relative                                                                           ED.sub.50 .sup.2                                                                     Relative                                                                           ED.sub.60 .sup.3                                                                     Relative                    Test Compound      (μg/pellet)                                                                       potency                                                                            (μg/pellet)                                                                       potency                                                                            (μg/pellet)                                                                       potency                     __________________________________________________________________________    Chloromethyl 11β-hydroxy-17α-                                                         307         460         690                                isopropoxycarbonyloxyandrost-                                                                           1           1           1                           4-en-one-17β-carboxylate                                                                    (238-394)   (360-623)    (523-1023)                        Chloromethyl 11β-hydroxy-17α-                                                         47          119         301                                isopropoxycarbonyloxyandrosta-                                                                          6.5         3.9         2.3                         1,4-dien-3-one-17β-carboxylate                                                              (15-85)      (60-202)   (178-627)                          Chloromethyl 17α-ethoxy-                                                                   0.47        1.07        2.44                               carbonyloxy-9α-fluoro-11β-                                                                   653         430         283                         hydroxy-16α-methylandrosta-1,4-                                                            (0.23-0.75) (0.66-1.59) (1.65-3.86)                        dien-3-one-17β-carboxylate                                               Chloromethyl 9α-fluoro-11β-                                                           0.25        0.97        3.75                               hydroxy-17α-isopropoxycarbonyloxy-                                                                1228        474         184                         16β-methylandrosta-1,4-dien-3-                                                              (0.004-0.886)                                                                             (0.08-2.31) (1.25-7.68)                        one-17β-carboxylate                                                      Chloromethyl 17α-ethoxycarbonyloxy-                                                        2.31        6.45        18.01                              9α-fluoro-11β-hydroxy-16β-                                                              133         71          38                          methylandrosta-1,4-dien-3-one-                                                                   (1.07-6.38)  (2.96-44.58)                                                                               (6.47-393.8)                     17β-carboxylate                                                          Chloromethyl 9α-fluoro-11β-                                                           0.58        1.20        2.49                               hydroxy-16α-methyl-17α-                                                                     529         383         277                         propoxycarbonyloxyandrosta-1,4-                                                                  (0.20-1.01) (0.67-2.88)  (1.37-13.32)                      dien-3-one-17β-carboxylate                                               Hydrocortisone     --     --   --     --   1015                               17-butyrate                                 (724-26866)                                                                         0.7                         Clobetasol         --     --   >3     --   >10    --                          17-propionate                                                                 __________________________________________________________________________     .sup.1 dose causing 40% inhibition of granulation tissue weight.              .sup.2 dose causing 50% inhibition of granulation tissue weight.              .sup.3 dose causing 60% inhibition of granulation tissue weight.              ( ) = 95% confidence limits                                              

THYMUS INHIBITION TESTING

Several further studies were undertaken to determine the effects ofselected compounds of the invention on thymi weights in rats when thedrugs were systemically administered. In each of these studies, maleSprague-Dawley rats were used. (For average weight of rats for eachstudy, see the tables which follow.) The test compounds were suspendedin 0.5% CMC (carboxymethylcellulose) and injected subcutaneously oncedaily for three days. On the fifth day (48 hours following the lasttreatment), the animals were sacrificed and the thymi weights wererecorded. Body weight gains were measured 24 hours after the lasttreatment. The test results are set forth in Tables VII, VIII and IXbelow. The TED₄₀ 's, TED₅₀ 's (thymolytic effective doses or dosesrequired to achieve 40% and 50% inhibition of thymi weight,respectively) and relative potency of representative compounds of theinvention and reference steroids are shown in Table X below. In Table X,the TED₄₀ and TED₅₀ for the reference steroid betamethasone 17-valeratehas each been assigned a value of 1, and the potencies of the othercompounds are expressed relative thereto. It is evident that the higherthe inhibition of thymus activity at a given dose, the more toxic thecompound is.

                                      TABLE VII                                   __________________________________________________________________________    Effects of systemically administereed (s.c.) soft steroids and reference      steroids                                                                      on body weight and thymus weight in rats.                                                   Dose   Number of                                                                            Body weight                                                                           Thymus Inhibition                         Test Compound (mg/kg/day)                                                                          Test Animals                                                                         gain (g)                                                                              (mg)   (%)                                __________________________________________________________________________    None (Control)        9      18.3 ± 0.7                                                                        471 ± 21                               Chloromethyl 11β-hydroxy-                                                              3       9      14.7 ± 0.6**                                                                      439 ± 18                                                                          6.8                                17α-isopropoxycarbonyloxy-                                                            10     10      10.2 ± 0.7***                                                                     386 ± 17**                                                                        18.0                               androst-4-en-3-one-17β-                                                                30     10      6.8 ± 2.1***                                                                      291 ± 22***                                                                       38.2                               carboxylate   100    10      2.8 ± 1.8***                                                                      185 ± 17***                                                                       60.7                               Chloromethyl 11β-hydroxy-                                                              3       9      9.0 ± 0.9***                                                                      377 ± 16**                                                                        20.0                               17α-isopropoxycarbonyl-                                                               10      9      6.2 ± 0.7***                                                                      312 ± 23***                                                                       33.8                               oxyandrosta-1,4-dien-3-                                                                     30     10      4.8 ± 1.4***                                                                      257 ± 24***                                                                       45.4                               one-17β-carboxylate                                                                    100    10      0.3 ± 1.6***                                                                      161 ± 19***                                                                       65.8                               Chloromethyl 17α-ethoxy-                                                              1      10      13.1 ± 1.0***                                                                     428 ± 20                                                                          9.1                                carbonyloxy-9α-fluoro-                                                                3       9      12.7 ± 1.4**                                                                      412 ± 20                                                                          12.5                               11β-hydroxy-16α-methyl-                                                          10     10      9.7 ± 1.3***                                                                      405 ± 21*                                                                         14.0                               androsta-1,4-dien-3-one-                                                                    30     10      4.4 ± 0.7***                                                                      292 ± 15***                                                                       38.0                               17β-carboxylate                                                          Hydrocortisone                                                                              0.3    10      17.0 ± 0.8                                                                        441 ± 27                                                                          6.4                                17-butyrate   1      10      11.8 ± 0.8***                                                                     323 ± 16***                                                                       31.4                                             3      10      7.3 ± 0.5***                                                                      166 ± 5***                                                                        64.8                                             10     10     -5.0 ± 1.1***                                                                       65 ± 5***                                                                        86.2                               Betamethasone 0.1    10      15.5 ± 0.9*                                                                       362 ± 16***                                                                       23.1                               17-valerate   0.3    10      12.4 ± 0.9***                                                                     276 ± 11***                                                                       41.4                                             1      10      13.0 ± 1.1***                                                                     200 ± 14***                                                                       57.5                                             3      10      9.9 ± 1.3***                                                                      119 ± 7***                                                                        74.7                               __________________________________________________________________________     *p < 0.05, **p < 0.01, ***p < 0.001 (Mean ± S.E.)                          Male SpragueDawley rats, weighing 149-168 g, were used.                  

                                      TABLE VIII                                  __________________________________________________________________________    Effects of systemically administered (s.c.) soft steroids and reference       steroids on body weight and                                                   thymus weight in rats.                                                                           Dose   Number of                                                                            Body weight                                                                           Thymus wt.                                                                           Inhibition                    Test Compound      (mg/kg/day)                                                                          Test Animals                                                                         gain (g)                                                                              (mg)   (%)                           __________________________________________________________________________    None (Control)            10      18.9 ± 0.6                                                                        550 ± 24                          Chloromethyl 17α-ethoxycarbonyloxy-                                                        10     7       14.2 ± 1.9                                                                        533 ± 31                                                                          3.1                           9α-fluoro-11β-hydroxy-16α-methyl-                            androsta-1,4-dien-3-one-17β-                                             carboxylate                                                                   Chloromethyl 9α-fluoro-11β-hydroxy-                                                   10     7        2.7 ± 1.9***                                                                     234 ± 31***                                                                       57.5                          17α-isopropoxycarbonyloxy-16α-                                    methylandrosta-1,4-dien-3-one-17β-                                       carboxylate                                                                   Chloromethyl 9α-fluoro-11β-hydroxy-                                                   10     7        5.3 ± 1.4***                                                                     260 ± 26***                                                                       52.7                          17α-isopropoxycarbonyloxy-16β-                                     methylandrosta-1,4-dien-3-one-17β-                                       carboxylate                                                                   Chloromethyl 17α-ethoxycarbonyloxy-                                                        10     7        2.4 ± 1.8***                                                                     266 ± 20***                                                                       51.6                          9α-fluoro-11β-hydroxy-16β-                                    methylandrosta-1,4-dien-3-one-17β-                                       carboxylate                                                                   Chloromethyl 9α-fluoro-11β-hydroxy-                                                   10     7        2.7 ± 1.7***                                                                     277 ± 25***                                                                       49.6                          16α-methyl-17α-propoxycarbonyloxy-                                androsta-1,4-dien-3-one-17β-carboxylate                                  Clobetasol         0.003  8       18.2 ± 0.6                                                                        537 ± 28                                                                          2.4                           17-propionate      0.01   8       15.5 ± 1.1*                                                                       498 ± 15                                                                          9.5                                              0.03   8       12.3 ± 1.3**                                                                      363 ± 22***                                                                       34.0                                             0.1    8       -0.4 ± 1.3***                                                                     149 ± 9***                                                                        72.9                                             0.3    8      -14.3 ± 1.3***                                                                      63 ± 3***                                                                        88.5                          __________________________________________________________________________     *p < 0.05, **p < 0.01, ***p < 0.001. (mean ± S.E.)                         Male SpragueDawley rats, weighing about 185 g (162-209 g), were used.    

                                      TABLE IX                                    __________________________________________________________________________    Effects of systemically administered (s.c.) soft steroids on body weight      and thymus weight in rats.                                                                     Dose   Number of                                                                            Body weight                                                                          Thymus wt.                                                                           Decrease                         Test Compound    (mg/kg/day)                                                                          Test Animals                                                                         gain (g)                                                                             (mg)   (%)                              __________________________________________________________________________    None (Control)          10     21.2 ± 0.9                                                                        426 ± 17                             Chloromethyl 9α-fluoro-11β-                                                          3     7      18.8 ± 1.4                                                                        426 ± 19                                                                          0.0                              hydroxy-17α-methoxycarbonyloxy-                                                          10     7      13.8 ± 1.6***                                                                     354 ± 8**                                                                         16.9                             16α-methylandrosta-1,4-dien-3-                                                           30     7      12.0 ± 0.8***                                                                     282 ± 11***                                                                       33.8                             one-17β-carboxylate                                                                       100    7       9.8 ± 1.3***                                                                     206 ± 15***                                                                       51.6                             Chloromethyl 9α-fluoro-11β-                                                          1     7      18.0 ± 1.5                                                                        387 ± 23                                                                          9.2                              hydroxy-16α-methyl-17α-                                                             3     7      15.6 ± 1.3**                                                                      347 ± 15**                                                                        18.5                             pentyloxycarbonyloxyandrosta-                                                                  10     7      17.4 ± 1.5*                                                                       357 ± 22*                                                                         16.2                             1,4-dien-3-one-17β-carboxylate                                                            30     7      13.5 ± 1.0***                                                                     335 ± 17**                                                                        21.4                             __________________________________________________________________________     *p < 0.05, **p < 0.01, ***p < 0.001 (Mean ± S.E.)                          Male SpragueDawley rats, weighing 91-112 g, were used.                   

                                      TABLE X                                     __________________________________________________________________________    Thymolytic activities of soft steroids administered subcutaneously to         rats.                                                                                            TED.sub.40                                                                           Relative                                                                           TED.sub.50                                                                           Relative                                Compound           (mg)   Potency                                                                            (mg)   Potency                                 __________________________________________________________________________    Chloromethyl 11β-hydroxy-                                                                   31.0        58.5                                           17α-isopropoxycarbonyloxyandrost-                                                                 0.01        0.01                                    4-en-3-one-17β-carboxylate                                                                  (23.9-41.9) (43.1-87.1)                                    Chloromethyl 11β-hydroxy-17α-                                                         16.2        35.3                                           isopropoxycarbonyloxyandrosta-                                                                          0.02        0.02                                    1,4-dien-3-one-17β-carboxylate                                                              (11.2-23.2) (24.6-57.5)                                    Chloromethyl 17α-ethoxycarbonyloxy-                                                        51.5        >51.5.sup.a                                    9α-fluoro-11β-hydroxy-16α-                                                             0.0058      <0.011                                  methylandrosta-1,4-dien-3-one-                                                                    (26.5-290.0)                                              17β-carboxylate                                                          Hydrocortisone     1.3    .sub.0.23                                                                          2.0    .sub.0.29                               17-butyrate        (1.1-1.5)   (1.7-2.3)                                      Betamethasone      0.30   .sub.1                                                                             0.58   .sub.1                                  17-valerate        (0.24-0.36) (0.49-0.69)                                    Clobetasol         0.035  .sub.8.6                                                                           0.052  .sub.11.2                               17-propionate      (0.030-0.039)                                                                             (0.046-0.059)                                  __________________________________________________________________________     .sup.a Even at a dosage level of 100 mg/kg/day, 50% reduction in thymus       weight could not be achieved.                                            

BLANK COTTON PELLET GRANULOMA ASSAY

A further test was undertaken to determine the thymolytic activity of arepresentative species of the invention as compared to betamethasone17-valerate. In this test, the drugs were administered intravenously torats, while using a blank cotton pellet granuloma assay. MaleSprague-Dawley rats, each weighing about 185 grams (166-196 grams), wereused. Two cotton pellets, each weighing 30 mg and containing no testcompounds, were sterilized and implanted subcutaneously into the back ofeach test animal. This day was considered day 0 of implantation. Testcompounds suspended in 0.8% polysorbate 80 were administeredintravenously once daily for 3 consecutive days beginning with day 1. Onday 5, the animals were sacrificed and the two pellets, with theirrespective granulomas, were removed, dried overnight in an oven at 50°C. and weighed (dry granuloma weight). The thymi and final body weightswere also recorded. The results are given in Table XI below.

In the foregoing tests, there was determined the deactivation of therepresentative species of the present soft steroids administeredintravenously to rats. The ratio between the potencies of the teststeroids and betamethasone 17-valerate against local anti-inflammationwas 283:0.7 as seen from Table VI. This means that the test compoundsexhibit a local anti-inflammatory activity which is approximately 400times as high as the activity of the betamethasone 17-valerate. The testcompounds were administered intravenously to rats to check the testcompounds also for systemic anti-inflammatory activity as compared tobetamethasone 17-valerate. The test compounds were found lower in theinhibition of granulation tissue formation and also in the thymusinvolution activity than betamethasone 17-valerate. From the results ofthe tests, it is presumed that the compounds which will not be readilysubjected to metabolism (deactivation) have a systemic anti-inflammatoryactivity, as is the case with betamethasone 17-valerate.

                                      TABLE XI                                    __________________________________________________________________________    Thymolytic activities of test steroids administered intravenously to rats     in the blank cotton pellet granuloma assay.                                                Dose   Number of                                                                             Body wt.                                                                              Dry granuloma                                                                         Inhibition                                                                          Thymus                                                                               Decrease             Test Compound                                                                              (mg/kg/day)                                                                          Test Animals                                                                          gain (g)                                                                              wt. (mg)                                                                              (%)   (mg)   (%)                  __________________________________________________________________________    None (Control)      7        21.4 ± 1.3                                                                        62.7 ± 6.1 422 ± 27                 Chloromethyl 17α-                                                                    1      7        14.1 ± 1.4**                                                                      50.1 ± 6.9                                                                         20.1  373 ± 25                                                                          11.6                 ethoxycarbonyloxy-9α-                                                                3      6        14.2 ± 1.3**                                                                      49.3 ± 5.1                                                                         21.4  338 ± 20*                                                                         19.9                 fluoro-11β-hydroxy-                                                                   10     6         0.3 ± 1.7***                                                                     45.7 ± 4.6                                                                         27.1  209 ± 31***                                                                       50.5                 16α-methylandrosta-                                                                  30     6       -18.5 ± 2.3***                                                                     32.7 ± 3.0**                                                                       47.8   71 ± 4***                                                                        83.2                 1,4-dien-3-one-17β-                                                      carboxylate                                                                   Betamethasone                                                                              0.1    7        14.4 ± 1.6**                                                                      49.3 ± 3.9                                                                         21.4  305 ± 14**                                                                        27.7                 17-valerate  0.3    5        12.2 ± 1.1***                                                                     44.4 ± 2.8*                                                                        29.2  288 ± 27**                                                                        31.8                              1      7        12.9 ± 1.1***                                                                     46.1 ± 4.3*                                                                        26.5  233 ± 15***                                                                       44.8                              3      7        13.0 ± 2.5*                                                                       47.3 ± 2.7                                                                         24.6  167 ± 22***                                                                       60.4                 __________________________________________________________________________     *p < 0.05, **p < 0.01, ***p < 0.001. (Mean ± S.E.)                    

The ED₅₀ 's calculated for the local cotton pellet granuloma assay (asshown, for example, in Table VI above) and the TED₄₀ 's calculated onthe basis of thymus inhibition testing (as shown, for example, in TableX above) were used to arrive at relative potency and a therapeutic indexfor representative species of the invention as compared to prior artsteroids. See Table XII below, which clearly shows the potentanti-inflammatory activity and minimal systemic toxicity of thecompounds of the present invention.

                                      TABLE XII                                   __________________________________________________________________________    Therapeutic Indices of representative species of the invention as             compared to prior art steroids.                                                                        Relative    Relative                                                                           Therapeutic                         Compound           ED.sub.50 .sup.a                                                                    Potency                                                                            TED.sub.40 .sup.b                                                                    Potency                                                                            Index.sup.c                         __________________________________________________________________________    Chloromethyl 11β-hydroxy-17α-                                                         460   1    31.0   1/24 24                                  isopropoxycarbonyloxyandrost-4-                                                                  (360-623)  (23.9-41.9)                                     en-3-one-17β-carboxylate                                                 Chloromethyl 11β-hydroxy-17α-                                                         119   4    16.2   1/12 48                                  isopropoxycarbonyloxyandrosta-                                                                    (60-202)  (11.2-23.2)                                     1,4-dien-3-one-17β-carboxylate                                           Chloromethyl 17α-ethoxycarbonyloxy-                                                        1.07  450  51.5   1/40 18000                               9α-fluoro-11β-hydroxy-16α-                                                      (0.66-1.59)                                                                               (26.5-290.0)                                   methylandrosta-1,4-dien-3-one-                                                17β-carboxylate                                                          Chloromethyl 9α-fluoro-11β-hydroxy-                                                   2.38  202  46.0   1/36 7270                                17α-methoxycarbonyloxy-16α-                                                          (1.60-3.78)                                                                              (36.0-62.1)                                     methylandrosta-1,4-dien-3-one-                                                17β-carboxylate                                                          Hydrocortisone     480   1    1.3    1     1                                  17-butyrate        (313-892)  (1.1-1.5)                                       Betamethasone      100   5    0.3    4     1                                  17-valerate                   (0.24-0.36)                                     __________________________________________________________________________     .sup.a for the antiinflammatory effect in cotton pellet granuloma             (μg/pellet)                                                                .sup.b for the thymus inhibition effect required subcutaneously (mg/kg)       .sup.c the ratio of the relative potency for the ED.sub.50 to the relativ     potency for the TED.sub.40 ; hydrocortisone 17butyrate has been assigned      value of one                                                             

The compounds of formula (I) can be combined with suitable non-toxicpharmaceutically acceptable carriers to provide pharmaceuticalcompositions for use in the treatment of topical or other localizedinflammation. Obviously, in view of their lack of systemic activity, thecompounds of the present invention are not intended for treatment ofconditions where systemic adrenocortical thereapy is indicated, e.g.,adrenocortical insufficiency. As examples of inflammatory conditionswhich can be treated with pharmaceutical compositions containing atleast one compound of the invention and one or more pharmaceuticalcarriers, the following can be mentioned. dermatological disorders suchas atopic dermatitis, acne, psoriasis or contact dermatitis; allergicstates such as bronchial asthma; ophthalmic and otic diseases involvingacute and chronic allergic and inflammatory reactions; respiratorydiseases; ulcerative colitis; and anorectal inflammation, pruritus andpain associated with hemorrhoids, proctitis, cryptitis, fissures,postoperative pain and pruritus ani. Such compositions may also beapplied locally as a propylactic measure against the inflammation andtissue rejection which arise in connection with transplants.

Obviously, the choice of carrier(s) and dosage forms will vary with theparticular condition for which the composition is to be administered.

Examples of various types of preparations for topical/localadministration include ointments, lotions, creams, powders, drops, (e.g.eye or ear drops), sprays, (e.g. for the nose or throat), suppositories,retention enemas, chewable or suckable tablets or pellets (e.g. for thetreatment of aphthous ulcers) and aerosols. Ointments and creams may,for example, be formulated with an aqueous or oily base with theaddition of suitable thickening and/or gelling agents and/or glycols.Such base may thus, for example, include water and/or an oil such asliquid paraffin or a vegetable oil such as arachis oil or castor oil, ora glycolic solvent such as propylene glycol or 1,3-butanediol.Thickening agents which may be used according to the nature of the baseinclude soft paraffin, aluminum stearate, cetostearyl alcohol,polyethylene glycols, woolfat, hydrogenated lanolin and beeswax and/orglyceryl monostearate and/or non-ionic emulsifying agents.

The solubility of the steroid in the ointment or cream may be enhancedby incorporation of an aromatic alcohol such as benzyl alcohol,phenylethyl alcohol or phenoxyethyl alcohol.

Lotions may be formulated with an aqueous or oily base and will ingeneral also include one or more of the following, namely, emulsifyingagents, dispersing agents, suspending agents, thickening agents,solvents, coloring agents and perfumes. Powders may be formed with theaid of any suitable powder base e.g. talc, lactose or starch. Drops maybe formulated with an aqueous base also comprising one or moredispersing agents, suspending agents or solubilizing agents, etc. Spraycompositions may, for example, be formulated as aerosols with the use ofa suitable propellane, e.g., dichlorodifluoromethane ortrichlorofluoromethane.

The proportion of active ingredient in the compositions according to theinvention will vary with the precise compound used, the type offormulation prepared and the particular condition for which thecomposition is to be administered. The formulation will generallycontain from about 0.0001 to about 5% by weight of the compound offormula (I). Topical preparations will generally contain 0.0001 to 2.5%,preferably 0.01 to 0.5%, and will be administered once daily, or asneeded. Also, generally speaking, the compounds of the invention can beincorporated into topical and other local compositions formulatedsubstantially as are such presently available types of compositionscontaining known glucocorticosteroids, at approximately the same (or inthe case of the most potent compounds of the invention, atproportionately lower) dosage levels as compared to known highly activeagents such as methyl prednisolone acetate and beclomethasonedipropionate or at considerably lower dosage levels as compared to lessactive known agents such as hydrocortisone.

Thus, for example, an inhalation formulation suitable for use in thetreatment of asthma can be prepared as a metered-dose aerosol unitcontaining a representative species of the invention such aschloromethyl17α/ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,according to procedures well-known to those skilled in the art ofpharmaceutical formulations. Such an aerosol unit may contain amicrocrystalline suspension of the aforementioned compound in suitablepropellants (e.g., trichlorofluoromethane and dichlorodifluoromethane),with oleic acid or other suitable dispersing agent. Each unit typicallycontains 10 milligrams of the aforesaid active ingredient, approximately50 micrograms of which are released at each actuation. When one of themore potent species of the invention, e.g. chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate,is employed, each unit typically contains 1 milligram of the activeingredient and releases approximately 5 micrograms at each actuation.

Another example of a pharmaceutical composition according to theinvention is a foam suitable for treatment of a wide variety ofinflammatory anorectal disorders, to be applied anally or perianally,comprising 0.1% of a compound of formula (I) such as chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrosta-4-en-3-one-17β-carboxylate,and 1% of a local anaesthetic such as pramoxine hydrochloride, in amucoadhesive foam base of propylene glycol, ethoxylated stearyl alcohol,polyoxyethylene-10-stearyl ether, cetyl alcohol, methyl paraben, propylparaben, triethanolamine, and water, with inert propellents. When a morepotent compound of the invention is employed, less active ingredientgenerally is used, e.g. 0.05% of chloromethyl9α-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate.

Yet another pharmaceutical formulation according to the invention is asolution or suspension suitable for use as a retention enema, a singledose of which typically contains 40 milligrams of a compound of theinvention such as chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate (or20 milligrams of a more potent compound of the invention such aschloromethyl9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylateor chloromethyl9α-fluoro-11β-hydroxy-16α-methyl-17α-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate)together with sodium chloride, polysorbate 80 and from 1 to 6 ounces ofwater (the water being added shortly before use). The suspension can beadministered as a retention enema or by continuous drip several timesweekly in the treatment of ulcerative colitis.

Other pharmaceutical formulations according to the invention areillustrated in the examples which follow.

Without further elaboration, it is believed that one of ordinary skillin the art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the following examples areto be construed as merely illustrative and not limitative of theremainder of the specification and claims in any way whatsoever.

EXAMPLE 1

To a solution of hydrocortisone (15 grams, 0.04 mol) in 120 millilitersof tetrahydrofuran and 30 milliliters of methanol at room temperature isadded a warm (approximately 50° C.) solution of sodium metaperiodate(25.7 grams, 0.12 mol) in 100 milliliters of water). The reactionmixture is stirred at room temperature for 2 hours, then is concentratedunder reduced pressure to remove the tetrahydrofuran and methanol. Thesolid is triturated with 50 milliliters of water, separated byfiltration, washed with water and dried in vacuo at 50° C. for 3 hours.The product, 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid(i.e., cortienic acid), melts at 231°-234° C., is obtained inapproximately 96% yield (13.76 grams), and can be represented by thestructural formula ##STR34##

EXAMPLE 2

To a cold solution of 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylicacid (5% weight/volume; 1 mol) and triethylamine (4 mol) indichloromethane is added a 50% (weight/volume) solution of methylchloroformate (3.9 mol) in dichloromethane. The reaction mixture isallowed to warm to room temperature over a 2 hour period. Thetriethylamine hydrochloride precipitate which forms is removed byfiltration and the filtration is washed successively with 3% sodiumbicarbonate, dilute (˜1%) hydrochloric acid and water. The organic layeris separated, dried with magnesium sulfate, and filtered. The filtrateis concentrated in vacuo to a foam. The foam is used in the next step(e.g., Example 3 below) or chromatographed and crystallized foranalysis. The product,11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylicacid, melts at 198°-204° C. after chromatography and crystallization; ir(KBr) 3000-2800 (C--H), 1750, 1735, 1720 (C═O), 1650, 1640 (C═C--C═O)cm⁻¹. The product can be represented by the structural formula ##STR35##

Substitution of an equivalent quantity of ethyl chloroformate for themethyl chloroformate employed above and substantial repetition of theforegoing procedure affords17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acid,melting at 192°-195° C. after chromatography and crystalization; ir(KBr) 3500 (11β-O--H), 3000-2800 (C--H), 1740 (C═O), 1630 (C═C--C═O)cm⁻¹, nmr(CDCl₃) δ6.4(1, b, COOH), 5.67(1, s, C--CH), 4.43 (1, b, CHOE),4.13 (2, q, J=7.5 Hz, OCH₂ CH₃); Anal. calcd. for C₂₃ H₃₂ O₇ : C, 65.69;H, 7.67. Found: C, 65.76; H, 7.74.

In a similar manner, substitution of an equivalent quantity of butylchloroformate for the methyl chloroformate employed in the fristparagraph of this example and substantial repetition of the procedurethere detailed affords17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acid.The final product, after crystallization from tetrahydrofuran-hexane,melts at 164°-166° C.

Similarly, substituting an equivalent amount of isopropyl chloroformatefor the methyl chloroformate used in the first paragraph of this exampleand repeating the procedure there detailed affords11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylicacid. The final product, after crystallization fromtetrahydrofuran-hexane, melts at 144.5°-146.5° C.

EXAMPLE 3

11β-Hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylic acidis combined with an equivalent amount of 1N sodium hydroxide in methanoland that solution is diluted to 100 times the original volume with ethylether. The suspension which results is refrigerated for 1 hour. Then,the crystals which form are removed by filtration, dried in an evacuateddesiccator, and dissolved in hexamethylphosphoramide (10%weight/volume). A portion of the resultant solution containing 1 mole ofthe acid salt, i.e. of sodium11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate, iscombined with 4 moles of chloromethyl iodide. The reaction mixture ismaintained at room temperature for 3 hours, then is diluted to 10 timesthe original volume with ethyl acetate. The diluted reaction mixture iswashed successively with 5% sodium thiosulfate, 3% sodium bicarbonate,and water. The organic layer is separated, dried with magnesium sulfateand filtered. The filtrate is concentrated in vacuo to a foam. The foamis purified by crystallization from a suitable solvent (ethyl ether ortetrahydrofuran/hexane). There is thus obtained chloromethyl11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate,melting at 171°-173° C. after crystallization; ir(KBr) 3000-2800 (C--H),1760, 1748 (C═O), 1650 (C═C--C═O) cm⁻¹ ; nmr (CDCl₃) δ5.67(s, 1, C═CH),5.82, 5.62 (ABq, J=5.5 Hz, 2, OCH₂ Cl), 4.47(b, 1, CHOH); Anal. calcd.for C₂₃ H₃₁ ClO: C, 60.72; H, 6.87; Cl, 7.79. Found: C, 60.50; H, 7.06;Cl, 7.50. The product is characterized by the structural formula##STR36##

Substitution of an equivalent quantity of17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acidfor the steroidal acid employed above and substantial repetition of theforegoing procedure affords, as the intermediate salt, sodium17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,and, as the final product, chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,melting at 197°-200° C. after crystallization; ir (KBr) 3600-3200(O--H), 3000-2800 (C--H), 1763, 1740 (C═O), 1650 (C═C--C═O) cm⁻¹ ; nmr(CDCl₃) δ5.7(s, 1, C═CH), 5.81, 5.62 (ABq, J=5 Hz, 2, --OCH₂ Cl); Analcalcd. for C₂₄ H₃₃ ClO₇ : C, 61.46; H, 7.09. Found: C, 61.58; H, 7.08.

In a similar manner, substitution of an equivalent quantity of17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acidfor the steroidal acid employed in the first paragraph of this exampleand substantial repetition of the procedure there detailed affords, asthe intermediate salt, sodium17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,and, as the final product, chloromethyl17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,melting at 98°-100° C. after crystallization; ir(KBr) 3600-3300 (O--H),3000-2800 (C--H), 1765 (O₂ C═O), 1735 (OC═O), 1650 (C═C--C═O) cm⁻¹ ;nmr(CDCl₃) δ5.60 (2, ABq, J=4.5 Hz, --OCH₂ Cl), 5.67 (1, s, C═CH), 4.45(1, b, CHOH), 4.08 (2, t, J=6 Hz, O₂ COCH₂ --CH₂); Anal calcd. for C₂₆H.sub. 37 ClO₇ : C, 62.77; H, 7.44; Cl, 7.14. Found: C, 62.88; H, 7.23;Cl, 7.30.

Similarly, substituting an equivalent amount of11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylicacid for the steroidal acid employed in the first paragraph of thisexample and substantial repetition of the procedure there detailedaffords, as the intermediate salt, sodium11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate,and, as the final product, chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate,melting at 183.5°-184.5° C. after recrystallization fromtetrahydrofuran-hexane.

In a similar manner, an equivalent quantity of17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acidis substituted for the steroidal acid and an equivalent quantity ofbutyl chloride is substituted for the chloromethyl iodide employed inthe first paragraph of this example; and the procedure there detailed issubstantially repeated, except that the step of washing with 5% sodiumthiosulfate is eliminated. Obtained in this manner are the intermediatesalt, sodium17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate, andthe final product, butyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate. Thefinal product after crystallization from acetone melts at 148°-149° C.;after chromatography and crystallization, ir(KBr) 3600-3200 (O--H),3000-2800 (C--H), 1750 (2 C═O), 1670 (C═C--C═O) cm⁻¹ ; nmr (CDCl₃)δ5.64(s, 1, --C═CH), 4.46 (b, 1, CHOH), 4.32-4.95 (m, 4, COOCH₂ CH₃ ⁺,COOCH₂ CH₂ --); Anal. calcd. for C₂₇ H₄₀ O₇ : C, 67.99; H, 8.39. Found:C, 67.76; H, 7.74.

EXAMPLE 4

17α-Ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acid(3 grams, 7.13 mmol6) is treated with 7.13 milliliters of 1M methanolicsodium hydroxide solution, and 500 milliliters of ethyl ether are thenadded to effect precipitation. The precipitate is separated byfiltration and dried in an evacuated dessicator overnight to afford 2.71grams (6.12 mmol) of the desired salt, i.e. sodium17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate, asa yellow powder. The salt is dissolved in 40 milliliters ofhexamethylphosphoramide and chloromethyl methyl sulfide (2.36 grams,24.5 mmol) is added slowly. A precipitate of sodium chloride forms inthe reaction mixture within 1 minute. The reaction mixture is stirred atroom temperature for 1 hour, then is diluted with ethyl acetate to atotal volume of 200 milliliters and washed successively with 3% sodiumbicarbonate and water. The organic layer is separated, dried withmagnesium sulfate and filtered. The filtrate is concentrated in vacuo toan oil, and the oil is chromatographed from silica gel, using ethylacetate, chloroform and acetic acid as eluants. The chromatographedproduct is crystallized from a mixture of ethyl ether and hexane to givewhite powdery crystals of methylthiomethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,melting at 133°-136° C. That product is characterized by the structuralformula ##STR37##

To a solution of methylthiomethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate(0.48 gram, 1 mmol) in 2 milliliters of dichloromethane is addedm-chloroperoxybenzoic acid (0.4 gram=0.34 gram of peracid, 2 mmol). Anexothermic reaction ensues, which subsides quickly. The reaction mixtureis stirred at room temperature for 1 hour. The precipitate which formsis removed by filtration and the filtrate is concentrated in vacuo toafford, as a white foam, methylsulfonylmethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate.That product has the structural formula ##STR38##

NMR (CDCl₃): δ5.07 (s, 2, OCH₂ SO₂), 2.97 (s, 3, SO₂ CH₃).

Repetition of the procedure described in the preceding paragraph, butusing only 1 mmol of m-chloroperoxybenzoic acid, affordsmethylsulfinylmethyl17β-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate.

EXAMPLE 5A

Substitution of an equivalent quantity of one of the starting materialslisted below for the hydrocortisone used in Example 1 and substantialrepetition of the procedure there detailed affords the indicatedproducts:

    ______________________________________                                        STARTING MATERIAL                                                                            PRODUCT                                                        ______________________________________                                        fludrocortisone                                                                              9α-fluoro-11β,17α-dihydroxy-                                 androst-4-en-3-one-17β-                                                  carboxylic acid,                                                              m.p. 250-253° C.                                        betamethasone  9α-fluoro-11β,17α-dihydroxy-                                 16β-methylandrosta-1,4-dien-                                             3-one-17β-carboxylic acid,                                               m.p. 248-249° C.                                        dexamethasone  9α-fluoro-11β,17α-dihydroxy-16α-                       methylandrosta-1,4-dien-3-one-                                                17β-carboxylic acid,                                                     m.p. 275-278.5° C.                                      ______________________________________                                    

EXAMPLE 5B

Substitution of an equivalent quantity of one of the starting materialslisted below for the hydrocortisone used in Example 1 and substantialrepetition of the procedure there detailed affords the indicatedproducts:

    ______________________________________                                        STARTING MATERIAL                                                                            PRODUCT                                                        ______________________________________                                        cortisone      17α-hydroxyandrost-4-en-3,11-                                           dione-17β-carboxylic acid                                 chloroprednisone                                                                             6α-chloro-17α-hydroxyandrosta-                                    1,4-dien-3,11-dione-17β-                                                 carboxylic acid                                                flumethasone   6α,9α-difluoro-11β, 17α-dihydroxy-                     16α-methylandrosta-1,4-dien-3-one-                                      17β-carboxylic acid                                       fluprednisolone                                                                              6α-fluoro-11β,17α-dihydroxy-                                 androsta-1,4-dien-3-one-17β-                                             carboxylic acid                                                meprednisone   17α-hydroxy-16β-methylandrosta-                                    1,4-dien-3,11-dione-17β-                                                 carboxylic acid                                                methyl prednisolone                                                                          11α,17β-dihydroxy-6α-methyl-                                 androsta-1,4-dien-3-one-17β-                                             carboxylic acid                                                paramethasone  6α-fluoro-11β,17α-dihydroxy-16α-                       methylandrosta-1,4-dien-3-one-                                                17β-carboxylic acid                                       prednisolone   11β,17α-dihydroxyandrosta-1,4-                                     dien-3-one-17β-carboxylic acid                            prednisone     17α-hydroxyandrosta-1,4-dien-                                           3,11-dione-17β-carboxylic acid                            triamcinolone  9α-fluoro-11β,16α,17α-trihydroxy-                      androsta-1,4-dien-3-one-17β-                                             carboxylic acid                                                ______________________________________                                    

EXAMPLE 6A

Following the general procedure of Example 2 and substituting thereinthe appropriate reactants affords the following novel intermediates ofthe present invention: ##STR39##

Compounds

    __________________________________________________________________________    Compound No.                                                                          R.sub.2                                                                              R.sub.3                                                                           R.sub.4                                                                         R.sub.5                                                                         Z     Δ                                                                         m.p.                                           __________________________________________________________________________    6A-1    CH.sub.2 C.sub.6 H.sub.5                                                             H   H H                                                                                ##STR40##                                                                          4 183-184° C. (ethanol)                   6A-2    C.sub.2 H.sub.5                                                                      H   F H                                                                                ##STR41##                                                                          4 190-191° C. (THF/hexane)                6A-3    C.sub.2 H.sub.5                                                                      β-CH.sub.3                                                                   F H                                                                                ##STR42##                                                                          1,4                                                                             128-129° C. (THF/hexane)                6A-4    C.sub.2 H.sub.5                                                                      α-CH.sub.3                                                                  F H                                                                                ##STR43##                                                                          1,4                                                                             143-144.5° C. (THF/hexane)              6A-5    iso-C.sub.3 H.sub.7                                                                  α-CH.sub.3                                                                  F H                                                                                ##STR44##                                                                          1,4                                                                             154.5-156° C. (THF/hexane)              6A-6    iso-C.sub.4 H.sub.9                                                                  H   H H                                                                                ##STR45##                                                                          4 125-126° C. (THF/hexane)                6A-7    iso-C.sub.3 H.sub.7                                                                  β-CH.sub.3                                                                   F H                                                                                ##STR46##                                                                          1,4                                                                             171.5-172.5° C. (THF/hexane)            6A-8    n-C.sub.3 H.sub.7                                                                    H   H H                                                                                ##STR47##                                                                          4 156-157° C. (THF/hexane)                6A-9    n-C.sub.3 H.sub.7                                                                    α-CH.sub.3                                                                  F H                                                                                ##STR48##                                                                          1,4                                                                             157-158° C. (THF/hexane)                6A-10                                                                                  ##STR49##                                                                           H   H H                                                                                ##STR50##                                                                          4 156-157.5° C. (ether/hexane)            6A-11   CH.sub.3                                                                             α-CH.sub.3                                                                  F H                                                                                ##STR51##                                                                          1,4                                                                             180-182° C. (ethyl acetate)             6A-12   n-C.sub.5 H.sub.11                                                                   α-CH.sub.3                                                                  F H                                                                                ##STR52##                                                                          1,4                                                                             138.5-139.5° C. (THF/hexane)            6A-13   C.sub.2 H.sub.5                                                                      α-CH.sub.3                                                                  F F                                                                                ##STR53##                                                                          1,4                                                                             157-158° C. (decomp.) (THF/hexane)      6A-14   C.sub.6 H.sub.5                                                                      α-CH.sub.3                                                                  F H                                                                                ##STR54##                                                                          1,4                                                                             246-248° C. (THF/hexane)                6A-15   CH.sub.2 CH.sub.2 Cl                                                                 α-CH.sub.3                                                                  F H                                                                                ##STR55##                                                                          4 93-94° C. (THF/hexane)                  __________________________________________________________________________     6 A-1 to 6A-15 above can be named as follows:

6A-1:17α-benzyloxoycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17.beta.-carboxylicacid

6A-2:17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxyandrost-4-en-3-one-17β-carboxylicacid

6A-3:17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6A-4:17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6A-5:9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6A-6:11β-hydroxy-17α-isobutoxycarbonyloxyandrost-4-en-3-one-17β-carboxylicacid

6A-7:9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6A-8:11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one-17β-carboxylic acid

6A-9:9α-fluoro-11β-hydroxy-16α-methyl-17α-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylicacid

6A-10:17α-cyclohexyloxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17.beta.-carboxylicacid

6A-11:9α-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicaicd

6A-12:9α-fluoro-11β-hydroxy-16α-methyl-17α-n-pentyloxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylicacid

6A-13:17α-ethoxycarbonyloxy-6α,9α-difluoro-11β-hydroxy-16α-methyllandrosta-1,4-dien-3-one-17β-carboxylicacid

6A-14:9α-fluoro-11β-hydroxy-16α-methyl-17α-phenoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylicacid

6A-15:17α-(2-chloroethoxycarbonyloxy)-9α-fluoro-11β-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

EXAMPLE 6B

Following the general procedure of Example 2 and substituting thereinthe appropriate reactants affords the following novel intermediates ofthe present invention: ##STR56##

    __________________________________________________________________________    Compound No.                                                                          R.sub.2   R.sub.3 R.sub.4                                                                         R.sub.5                                                                          Z     Δ                                  __________________________________________________________________________    6B-1    C.sub.2 H.sub.5                                                                         H       H H                                                                                      4                                        6B-2    CH.sub.3  H       H H                                                                                 ##STR57##                                                                          4                                        6B-3    CH.sub.3  H       F H                                                                                 ##STR58##                                                                          4                                        6B-4    C.sub.2 H.sub.5                                                                         α-CH.sub.3                                                                      F F                                                                                 ##STR59##                                                                          1,4                                      6B-5    C.sub.2 H.sub.5                                                                         H       H F                                                                                 ##STR60##                                                                          1,4                                      6B-6    C.sub.2 H.sub.5                                                                         β-CH.sub.3                                                                       H H                                                                                 ##STR61##                                                                          1,4                                      6B-7    CH.sub.2 CCl.sub.3                                                                      H       H H                                                                                 ##STR62##                                                                          4                                        6B-8    C.sub.2 H.sub.5                                                                         α-CH.sub.3                                                                      H F                                                                                 ##STR63##                                                                          1,4                                      6B-9    C.sub.2 H.sub.5                                                                         H       H H                                                                                 ##STR64##                                                                          1,4                                      6B-10   C.sub.2 H.sub.5                                                                         H       H H                                                                                 ##STR65##                                                                          1,4                                      6B-11   C.sub.2 H.sub.5                                                                         α-OCOOC.sub.2 H.sub.5                                                           F H                                                                                 ##STR66##                                                                          1,4                                      6B-12   CH.sub.2 Cl                                                                             α-CH.sub.3                                                                      F H                                                                                 ##STR67##                                                                          1,4                                      6B-13   CH.sub.2 CH.sub.2 Cl                                                                    α-CH.sub.3                                                                      F H                                                                                 ##STR68##                                                                          1,4                                      6B-14   C.sub.2 H.sub.5                                                                         H       H Cl                                                                                ##STR69##                                                                          1,4                                      6B-15   C.sub.6 H.sub.5                                                                         H       H H                                                                                 ##STR70##                                                                          4                                        6B-16                                                                                  ##STR71##                                                                              H       H H                                                                                 ##STR72##                                                                          4                                        6B-17                                                                                  ##STR73##                                                                              H       H H                                                                                 ##STR74##                                                                          4                                        6B-18   CHCH.sub.2                                                                              H       H H                                                                                 ##STR75##                                                                          4                                        6B-19   CH.sub.2 OCH.sub.3                                                                      H       H H                                                                                 ##STR76##                                                                          4                                        6B-20   CH.sub.2 SCH.sub.3                                                                      H       H H                                                                                 ##STR77##                                                                          4                                        6B-21   CH.sub.2 CH.sub.2 NHCOCH.sub.3                                                          H       H H                                                                                 ##STR78##                                                                          4                                        6B-22   CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           H       H H                                                                                 ##STR79##                                                                          4                                        6B-23   C.sub.2 H.sub.5                                                                         H       H CH.sub.3                                                                          ##STR80##                                                                          1,4                                      6B-24   CH.sub.2 SO.sub.2 CH.sub.3 *                                                            H       H H                                                                                 ##STR81##                                                                          4                                        6B-25   CH.sub.2 SOCH.sub.3 *                                                                   H       H H                                                                                 ##STR82##                                                                          4                                        __________________________________________________________________________     *prepared from 6B20 by subsequent reaction with .sub.--mchloroperbenzoic      acid.                                                                    

EXAMPLE 6C

Following the general procedure of Example 2 and substituting thereinthe appropriate reactants affords the following novel intermediates ofthe present invention: ##STR83##

    __________________________________________________________________________    Compound No.                                                                          R.sub.2  R.sub.3                                                                           R.sub.4                                                                         R.sub.5                                                                         Z     Δ                                                                         m.p.                                         __________________________________________________________________________    6C-1    CH.sub.2 CHCH.sub.2                                                                    α-CH.sub.3                                                                  F H                                                                                     1,4                                                                             227-229° C. (THF/hexane)              6C-2    CH.sub.2 CH.sub.2 CH.sub.3                                                             α-CH.sub.3                                                                  F F                                                                                ##STR84##                                                                          1,4                                                                             148-155° C. (decomp.) (ethanol/wat                                     er)                                          6C-3                                                                                   ##STR85##                                                                             α-CH.sub.3                                                                  F F                                                                                ##STR86##                                                                          1,4                                                                             157-159° C. (ethanol/water)           6C-4    C.sub.2 H.sub.5                                                                        α-CH.sub.3                                                                  H F                                                                                ##STR87##                                                                          1,4                                                                             105-108° C. (THF/n-hexane)            6C-5    (CH.sub.2).sub.2 CH.sub.3                                                              α-CH.sub.3                                                                  H F                                                                                ##STR88##                                                                          1,4                                                                             150-152° C. (THF/n-hexane)            6C-6                                                                                   ##STR89##                                                                             α-CH.sub.3                                                                  H F                                                                                ##STR90##                                                                          1,4                                                                             124-127° C. (THF/n-hexane)            6C-7    CH.sub.3 H   H H                                                                                ##STR91##                                                                          1,4                                                                             178-180° C. (THF/n-hexane)            6C-8    CH.sub.3 α-CH.sub.3                                                                  H F                                                                                ##STR92##                                                                          1,4                                                                             182-183° C. (THF/n-hexane)            6C-9    C.sub.2 H.sub.5                                                                        H   H H                                                                                ##STR93##                                                                          1,4                                                                             153-156° C. (THF/n-hexane)            6C-10   CH.sub.3 β-CH.sub.3                                                                   F H                                                                                ##STR94##                                                                          1,4                                                                             186-188 (decomposition) (THF/n-hexane)       6C-11   CH.sub.2 CH.sub.2 CH.sub.3                                                             β-CH.sub.3                                                                   F H                                                                                ##STR95##                                                                          1,4                                                                             143-144.5° C. (THF/n-hexane)          __________________________________________________________________________

The foregoing compounds can be named as follows:

6C-1:17α-allyloxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6C-2:6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylicacid

6C-3:6α,9α-difluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6C-4:17α-ethoxycarbonyloxy-6α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6C-5:6α-fluoro-11β-hydroxy-16α-methyl-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylicacid

6C-6:6α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6C-7:11β-hydroxy-17α-methoxycarbonyloxyandrosta-1,4-dien-3-one-17.beta.-carboxylicacid

6C-8:6α-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6C-9:17α-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17.beta.-carboxylicacid

6C-10:9α-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylicacid

6C-11:9α-fluoro-11β-hydroxy-16β-methyl-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylicacid

EXAMPLE 7A

Following the general procedure of Example 3 and substituting thereinthe appropriate reactants affords the following compounds: ##STR96##

    __________________________________________________________________________    Compound No.                                                                          R.sub.1                                                                              R.sub.2   R.sub.3                                                                              R.sub.4                                                                         R.sub.5                                                                         Z      Δ                                                                         m.p.                             __________________________________________________________________________    7A-1    CH.sub.2 Cl                                                                          C.sub.2 H.sub.5                                                                         H      F H                                                                                      4 228-229° C. (THF/hexan                                                 e)                               7A-2    CH.sub.2 Cl                                                                          C.sub.2 H.sub.5                                                                         β-CH.sub.3                                                                      F H                                                                                ##STR97##                                                                           1,4                                                                             220-221° C. (THF/hexan                                                 e)                               7A-3    CH.sub.2 Cl                                                                          C.sub.2 H.sub.5                                                                         α-CH.sub.3                                                                     F H                                                                                ##STR98##                                                                           1,4                                                                             230-235° C. (THF/hexan                                                 e)                               7A-4    CH.sub.2 Cl                                                                          C.sub.2 H.sub.5                                                                         H      H H                                                                                ##STR99##                                                                           1,4                                                                             220.5-223.5° C.                                                        (THF/hexane)                     7A-5    CH.sub.2 Cl                                                                          iso-C.sub.3 H.sub.7                                                                     H      H H                                                                                ##STR100##                                                                          1,4                                                                             197-198° C. (THF/hexan                                                 e)                               7A-6    CH.sub.2 Cl                                                                          C.sub.2 H.sub.5                                                                         H      F H                                                                                ##STR101##                                                                          1,4                                                                             245-248° C. (THF/hexan                                                 e)                               7A-7    CH.sub.2 Cl                                                                          iso-C.sub.3 H.sub.7                                                                     α-CH.sub.3                                                                     F H                                                                                ##STR102##                                                                          1,4                                                                             184.5-186° C.                                                          (THF/hexane)                     7A-8    CH.sub.2 Cl                                                                          iso-C.sub.3 H.sub.7                                                                     β-CH.sub.3                                                                      F H                                                                                ##STR103##                                                                          1,4                                                                             174-175.5° C. (THF)       7A-9    CH.sub.2 Cl                                                                          iso-C.sub.4 H.sub.9                                                                     H      H H                                                                                ##STR104##                                                                          4 140-141° C. (THF/isopr                                                 opyl ether)                      7A-10   CH.sub.2 Cl                                                                           ##STR105##                                                                             H      H H                                                                                ##STR106##                                                                          4 148-150° C. (isopropyl                                                   ether hexane)                  7A-11   CH.sub.2 Cl                                                                          n-C.sub.3 H.sub.7                                                                       H      H H                                                                                ##STR107##                                                                          4 181-182° C. (THF/hexan                                                 e)                               7A-12   CH.sub.2 Cl                                                                          n-C.sub.3 H.sub.7                                                                       α-CH.sub.3                                                                     F H                                                                                ##STR108##                                                                          1,4                                                                             176-176.5° C.                                                          (THF/hexane)                     7A-13   CH.sub.3                                                                             iso-C.sub.3 H.sub.7                                                                     H      H H                                                                                ##STR109##                                                                          4 211.5-213.5° C.                                                        (THF/hexane)                     7A-14   CH.sub.2 OC.sub.2 H.sub.5                                                            iso-C.sub.3 H.sub.7                                                                     H      H H                                                                                ##STR110##                                                                          4 137-138° C. (THF/hexan                                                 e)                               7A-15   CH.sub.2 Cl                                                                           ##STR111##                                                                             H      H H                                                                                ##STR112##                                                                          4 182-183° C. (ethanol)     7A-16*                                                                                 ##STR113##                                                                          iso-C.sub.3 H.sub.7                                                                     H      H H                                                                                ##STR114##                                                                          4 181-182.5° C.                                                          (THF/hexane)                              ##STR115##                                                                          iso-C.sub.3 H.sub.7                                                                     H      H H                                                                                ##STR116##                                                                          4 199-200° C. (THF/hexan                                                 e)                               7A-17   CH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                    iso-C.sub.3 H.sub.7                                                                     H      H H                                                                                ##STR117##                                                                          4 73-74° C. (isopropyl                                                   ether)                           7A-18*                                                                                 ##STR118##                                                                          iso-C.sub.3 H.sub.7                                                                     β-CH.sub.3                                                                      F H                                                                                ##STR119##                                                                          1,4                                                                             167.5-169° C.                                                          (THF/hexane)                              ##STR120##                                                                          iso-C.sub.3 H.sub.7                                                                     β-CH.sub.3                                                                      F H                                                                                ##STR121##                                                                          1,4                                                                             163-164° C. (THF/hexan                                                 e)                               7A-19   CH.sub.2 Cl                                                                          iso-C.sub.3 H.sub.7                                                                     β-CH.sub.3                                                                      F H                                                                                ##STR122##                                                                          1,4                                                                             200-201° C. (THF/iso-                                                  ropyl ether)                     7A-20   CH.sub.2 Cl                                                                          C.sub. 2 H.sub.5                                                                        α-CH.sub.3                                                                     F H                                                                                ##STR123##                                                                          1,4                                                                             138-140° C. (THF/iso-                                                  ropyl ether)                     7A-21   CH.sub.2 Cl                                                                          CH.sub.3  α-CH.sub.3                                                                     F H                                                                                ##STR124##                                                                          1,4                                                                             260-263° C. (THF/hexan                                                 e)                               7A-22   CH.sub.2 F                                                                           iso-C.sub.3 H.sub.7                                                                     H      H H                                                                                ##STR125##                                                                          4 207.5-210° C.                                                          (THF/hexane)                     7A-23   CH.sub.2 Cl                                                                          n-C.sub.5 H.sub.11                                                                      α-CH.sub.3                                                                     F H                                                                                ##STR126##                                                                          1,4                                                                             176-177° C. (THF/hexan                                                 e)                               7A-24   CH.sub.2 Cl                                                                          C.sub.2 H.sub.5                                                                          ##STR127##                                                                          H F                                                                                ##STR128##                                                                          1,4                                                                             153-154° C. (THF/hexan                                                 e)                               7A-25   CH.sub.2 F                                                                           C.sub.2 H.sub.5                                                                         α-CH.sub.3                                                                     F H                                                                                ##STR129##                                                                          1,4                                                                             239-240.5° C.                                                          (THF/hexane)                     7A-26   CH.sub.2 OCOCH.sub.3                                                                 C.sub.2 H.sub.5                                                                         H      H H                                                                                ##STR130##                                                                          4                                                                                ##STR131##                      7A-27   CH.sub.2 Cl                                                                          C.sub.2 H.sub.5                                                                         α-CH.sub.3                                                                     F F                                                                                ##STR132##                                                                          1,4                                                                             195-197° C. (THF/hexan                                                 e)                               7A-28   CH.sub.2 CH.sub.2 Cl                                                                 C.sub.2 H.sub.5                                                                         α-CH.sub.3                                                                     F H                                                                                ##STR133##                                                                          1,4                                                                             243-245° C. (THF/hexan                                                 e)                               7A-29   CH.sub.3                                                                             C.sub.2 H.sub.5                                                                         α-CH.sub.3                                                                     F H                                                                                ##STR134##                                                                          1,4                                                                             258.5-262.5° C.                                                        (THF/hexane)                     7A-30   CH.sub.2 CH.sub.2 Cl                                                                 iso-C.sub.3 H.sub.7                                                                     H      H H                                                                                ##STR135##                                                                          4 188.5-189.5° C.                                                        (THF/hexane)                     __________________________________________________________________________     *diastereomers                                                           

The foregoing compounds can be named as follows:

7A-1: chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxyandrost-4-en-3-one-17β-carboxylate

7A-2: chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylate

7A-3: chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7A-4: chloromethyl17β-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17.beta.-carboxylate

7A-5: chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate

7A-6: chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate

7A-7: chloromethyl9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7A-8: chloromethyl9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylate

7A-9: chloromethyl11β-hydroxy-17α-isobutoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate

7A-10: chloromethyl17α-cyclohexyloxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17.beta.-carboxylate

7A-11: chloromethyl11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate

7A-12: chloromethyl9α-fluoro-11β-hydroxy-16α-methyl-17α-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate

7A-13: methyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate

7A-14: ethoxymethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate

7A-15: chloromethyl17α-benzyloxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate

7A-16: 1-chloroethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate

7A-17: ethoxycarbonylmethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.carboxylate

7A-18: 1-chloroethyl9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylate

7A-19: chloromethyl9α-fluoro-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-dien-3,11-dione-17-carboxylate

7A-20: chloromethyl9α-fluoro-17α-isopropoxycarbonyloxy-16α-methylandrosta-1,4-dien-3,11-dione-17-carboxylate

7A-21: chloromethyl9α-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16α-methylandrost-1,4-dien-3-one-17β-carboxylate

7A-22: fluoromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate

7A-23: chloromethyl9α-fluoro-11β-hydroxy-16α-methyl-17α-pentyloxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate

7A-24: chloromethyl16α,17α-di(ethoxycarbonyloxy)-6α-fluoro-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate

7A-25: fluoromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7A-26: acetoxymethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate

7A-27: chloromethyl17α-ethoxycarbonyloxy-6α,9α-difluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7A-28: 2-chloroethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7A-29: methyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7A-30: 2-chloroethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate

EXAMPLE 7B

Following the general procedure of Examples 3 or 4 and substitutingtherein the appropriate reactants affords the following comppounds:##STR136##

    __________________________________________________________________________    Compound No.                                                                          R.sub.1   R.sub.2    R.sub.3  R.sub.4                                                                          R.sub.5                                                                           Z      Δ                   __________________________________________________________________________    7B-1    C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                          H        H  H                                                                                        4                         7B-2    C.sub.4 H.sub.9                                                                         CH.sub.2 C.sub.6 H.sub.5                                                                 H        H  H                                                                                  ##STR137##                                                                          4                         7B-3    CH.sub.2 COOC.sub.2 H.sub.5                                                             C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR138##                                                                          4                         7B-4    CH.sub.2 OCOCH.sub.3                                                                    C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR139##                                                                          4                         7B-5    CH.sub.2 Cl                                                                             C.sub.6 H.sub.5                                                                          H        H  H                                                                                  ##STR140##                                                                          4                         7B-6    CH.sub.2 Cl                                                                              ##STR141##                                                                              H        H  H                                                                                  ##STR142##                                                                          4                         7B-7    CH.sub.2 Cl                                                                             CH.sub.2 SCH.sub.3                                                                       H        H  H                                                                                  ##STR143##                                                                          4                         7B-8    C.sub.4 H.sub.9                                                                         C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR144##                                                                          4                         7B-9    CH.sub.2 Cl                                                                             CH.sub.3   H        H  H                                                                                  ##STR145##                                                                          4                         7B-10   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR146##                                                                          4                         7B-11   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR147##                                                                          4                         7B-12   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR148##                                                                          4                         7B-13   CH.sub.2 SOCH.sub.3                                                                     C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR149##                                                                          4                         7B-14   CH.sub.2 Cl                                                                             CH.sub.3   H        F  H                                                                                  ##STR150##                                                                          4                         7B-15   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          H        F  H                                                                                  ##STR151##                                                                          4                         7B-16   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          H        F  H                                                                                  ##STR152##                                                                          4                         7B-17   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          β-CH.sub.3                                                                        F  H                                                                                  ##STR153##                                                                          1,4                       7B-18   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          β-CH.sub.3                                                                        F  H                                                                                  ##STR154##                                                                          1,4                       7B-19   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          H        H  Cl                                                                                 ##STR155##                                                                          1,4                       7B-20   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          H        H  Cl                                                                                 ##STR156##                                                                          1,4                       7B-21   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          H        H  Cl                                                                                 ##STR157##                                                                          1,4                       7B-22   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          α-CH.sub.3                                                                       F  H                                                                                  ##STR158##                                                                          1,4                       7B-23   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          α-CH.sub.3                                                                       F  H                                                                                  ##STR159##                                                                          1,4                       7B-24   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          α-CH.sub.3                                                                       F  F                                                                                  ##STR160##                                                                          1,4                       7B-25   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          α-CH.sub.3                                                                       F  F                                                                                  ##STR161##                                                                          1,4                       7B-26   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          α-CH.sub.3                                                                       F  F                                                                                  ##STR162##                                                                          1,4                       7B-27   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          H        H  F                                                                                  ##STR163##                                                                          1,4                       7B-28   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          H        H  F                                                                                  ##STR164##                                                                          1,4                       7B-29   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub. 5                                                                         H        H  F                                                                                  ##STR165##                                                                          1,4                       7B-30   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          β-CH.sub.3                                                                        H  H                                                                                  ##STR166##                                                                          1,4                       7B-31   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          β-CH.sub.3                                                                        H  H                                                                                  ##STR167##                                                                          1,4                       7B-32   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          β-CH.sub.3                                                                        H  H                                                                                  ##STR168##                                                                          1,4                       7B-33   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          H        H  CH.sub.3                                                                           ##STR169##                                                                          1,4                       7B-34   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          H        H  CH.sub.3                                                                           ##STR170##                                                                          1,4                       7B-35   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          H        H  CH.sub.3                                                                           ##STR171##                                                                          1,4                       7B-36   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          α-CH.sub.3                                                                       H  F                                                                                  ##STR172##                                                                          1,4                       7B-37   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          α-CH.sub.3                                                                       H  F                                                                                  ##STR173##                                                                          1,4                       7B-38   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          α-CH.sub.3                                                                       H  F                                                                                  ##STR174##                                                                          1,4                       7B-39   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR175##                                                                          1,4                       7B-40   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR176##                                                                          1,4                       7B-41   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR177##                                                                          1,4                       7B-42   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR178##                                                                          1,4                       7B-43   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR179##                                                                          1,4                       7B-44   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          α-OCOOC.sub.2 H.sub.5                                                            F  H                                                                                  ##STR180##                                                                          1,4                       7B-45   CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                          α-OCOOC.sub.2 H.sub.5                                                            F  H                                                                                  ##STR181##                                                                          1,4                       7B-46   CH.sub.2 SO.sub.2 CH.sub.3                                                              C.sub.2 H.sub.5                                                                          α-OCOOC.sub.2 H.sub.5                                                            F  H                                                                                  ##STR182##                                                                          1,4                       7B-47   CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                          α-OH                                                                             H  F                                                                                  ##STR183##                                                                          1,4                       7B-48   CH.sub.2 Cl                                                                              ##STR184##                                                                              α-CH.sub.3                                                                       F  H                                                                                  ##STR185##                                                                          1,4                       7B-49   CH.sub.2 Cl                                                                             CH.sub.2 CH.sub.2 Cl                                                                     α-CH.sub.3                                                                       F  H                                                                                  ##STR186##                                                                          1,4                       7B-50   CH.sub.3  CH.sub.2 Cl                                                                              α-CH.sub.3                                                                       F  H                                                                                  ##STR187##                                                                          1,4                       7B-51   C.sub.4 H.sub.9                                                                         CH.sub.2 CCl.sub.3                                                                       H        H  H                                                                                  ##STR188##                                                                          4                         7B-52   CH.sub.2 CON(C.sub.2 H.sub.5).sub.2                                                     C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR189##                                                                          4                         7B-53                                                                                  ##STR190##                                                                             CH.sub.3   H        H  H                                                                                  ##STR191##                                                                          4                         7B-54   C.sub.6 H.sub.5                                                                         C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR192##                                                                          4                         7B-55   CH.sub.2 C.sub.6 H.sub.5                                                                CH.sub.3   H        H  H                                                                                  ##STR193##                                                                          4                         7B-56                                                                                  ##STR194##                                                                             C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR195##                                                                          4                         7B-57   CH.sub. 2 Cl                                                                             ##STR196##                                                                              H        H  H                                                                                  ##STR197##                                                                          4                         7B-58   CH.sub.2 Cl                                                                             CHCH.sub.2 H        H  H                                                                                  ##STR198##                                                                          4                         7B-59   CH.sub.2 Cl                                                                             CH.sub.2 OCH.sub.3                                                                       H        H  H                                                                                  ##STR199##                                                                          4                         7B-60   CH.sub.2 Cl                                                                             CH.sub.2 CH.sub.2 NHCOCH.sub.3                                                           H        H  H                                                                                  ##STR200##                                                                          4                         7B-61   CH.sub.2 Cl                                                                             CH.sub.2 CH.sub.2 OCOCH.sub.3                                                            H        H  H                                                                                  ##STR201##                                                                          4                         7B-62                                                                                  ##STR202##                                                                             C.sub.2 H.sub.5                                                                          H        H  H                                                                                  ##STR203##                                                                          4                         7B-63   CH.sub.2 Cl                                                                             CH.sub.2 SO.sub.2 CH.sub.3 *                                                             H        H  H                                                                                  ##STR204##                                                                          4                         7B-64   CH.sub.2 Cl                                                                             CH.sub.2 SOCH.sub.3 *                                                                    H        H  H                                                                                  ##STR205##                                                                          4                         __________________________________________________________________________     *prepared from Example 6B24 and 6B25 respectively by reaction with            ClCH.sub.2 I, or from Example 7B7 by reaction with                            .sub.--mchloroperbenzoic acid.                                           

EXAMPLE 7C

Following the general procedure of Example 3 and substituting thereinthe appropriate reactants affords the following compounds: ##STR206##

    __________________________________________________________________________    Compound                                                                      No.   R.sub.1                                                                              R.sub.2 R.sub.3                                                                           R.sub.4                                                                         R.sub.5                                                                         Z     Δ                                                                         m.p.                                     __________________________________________________________________________    7C-1  CH.sub.2 Cl                                                                                  α-CH.sub.3                                                                  F F                                                                                ##STR207##                                                                         1,4                                                                             222-224° C. (THF/hexane)          7C-2  CH.sub.2 Cl                                                                          CH.sub.2 CH.sub.2 CH.sub.3                                                            α-CH.sub.3                                                                  F F                                                                                ##STR208##                                                                         1,4                                                                             180.5-181.5° C. (THF/hexane)      7C-3  CH.sub.2 F                                                                           CH.sub.2 CH.sub.2 CH.sub.3                                                            α-CH.sub.3                                                                  F H                                                                                ##STR209##                                                                         1,4                                                                             165-165.5° C. (THF/hexane)        7C-4  CH.sub.2 CH.sub.2 Cl                                                                  ##STR210##                                                                           H   H H                                                                                ##STR211##                                                                         1,4                                                                             188.5-189.5° C. (THF/hexane)      7C-5  CH.sub.3                                                                             CH.sub.2 CH.sub.2 Cl                                                                  α-CH.sub.3                                                                  F H                                                                                ##STR212##                                                                         1,4                                                                             223-227° C. (isopropanol)         7C-6  CH.sub.2 Cl                                                                          C.sub.2 H.sub.5                                                                       α-CH.sub.3                                                                  H F                                                                                ##STR213##                                                                         1,4                                                                             153.5-154.5° C. (THF/n-hexane)                                         N                                        7C-7  CH.sub.2 Cl                                                                          (CH.sub.2).sub.2 CH.sub.3                                                             α-CH.sub.3                                                                  H F                                                                                ##STR214##                                                                         1,4                                                                             98.5-99.5° C. (ethyl                                                   acetate/n-hexane)                        7C-8  CH.sub.2 Cl                                                                           ##STR215##                                                                           α-CH.sub.3                                                                  H F                                                                                ##STR216##                                                                         1,4                                                                             124.5-126° C. (ethyl                                                   acetate/n-hexane)                        7C-9   CH.sub.2 Cl                                                                         (CH.sub.2).sub.2 CH.sub.3                                                             H   H H                                                                                ##STR217##                                                                         1,4                                                                             180.5-181.5° C. (THF/n-hexane)                                         O                                        7C-10 CH.sub.2 Cl                                                                          CH.sub.3                                                                              H   H H                                                                                ##STR218##                                                                         1,4                                                                             235-237° C. (THF/n-hexane)        7C-11 CH.sub.2 Cl                                                                          CH.sub.3                                                                              α-CH.sub.3                                                                  H F                                                                                ##STR219##                                                                         1,4                                                                             244.5-245.5° C. (THF/n-hexane)                                         O                                        7C-12 CH.sub.2 Cl                                                                          CH.sub.3                                                                              β-CH.sub.3                                                                   F H                                                                                ##STR220##                                                                         1,4                                                                             236-236.5° C. (THF/n-hexane)      7C-13 CH.sub.2 Cl                                                                          CH.sub.2 CH.sub.2 CH.sub.3                                                            β-CH.sub.3                                                                   F H                                                                                ##STR221##                                                                         1,4                                                                             183.5-184° C. (THF/n-hexane)      __________________________________________________________________________

The foregoing compounds can be named as follows:

7C-1: chloromethyl6α,9α-difluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7C-2: chloromethyl6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate

7C-3: fluoromethyl9α-fluoro-11β-hydroxy-16α-methyl-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate

7C-4: 2-chloroethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate

7C-5: methyl17α-(2-chloroethoxy)carbonyloxy-9α-fluoro-11β-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17β-carboxylate

7C-6: chloromethyl17α-ethoxycarbonyloxy-6α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7C-7: chloromethyl6α-fluoro-11β-hydroxy-16α-methyl-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate

7C-8: chloromethyl6α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7C-9: chloromethyl11β-hydroxy-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17.beta.-carboxylate

7C-10: chloromethyl11β-hydroxy-17α-methoxycarbonyloxyandrosta-1,4-dien-3-one-17.beta.-carboxylate

7C-11: chloromethyl6α-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

7C-12: chloromethyl9α-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylate

7C-13: chloromethyl9α-fluoro-11β-hydroxy-16β-methyl-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate

EXAMPLE 8

An equivalent quantity of11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid is substitutedfor the11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylic acidstarting material employed in Example 3, and the procedure of the firstparagraph of that example is substantially repeated. There are thusobtained, as the intermediate salt, sodium11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate, and, as the finalproduct, chloromethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate, melting at184°-186° C. (recrystallization from tetrahydrofuran-ether-hexane).

EXAMPLE 9

An equivalent quantity of11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid is substitutedfor the17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acidstarting material employed in Example 4, and the procedure of the firstparagraph of that example is substantially repeated. There are thusobtained, as the intermediate salt, sodium11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate, and, as the finalproduct, methylthiomethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate

Substitution of an equivalent quantity of methylthiomethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate for themethylthiomethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate usedin the second paragraph of Example 4 and substantial repetition of theprocedure there detailed affords methylsulfonylmethyl11α,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate.

EXAMPLE 10A

The procedure of each paragraph of Example 2 is substantially repeated,substituting an equivalent quantity of each of the following startingmaterials for the steroids employed therein: chloromethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate; andmethylthiomethyl 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate.The following soft anti-inflammatory agents of formula (I) are obtained:

    ______________________________________                                         ##STR222##                                                                   Compound No.                                                                            R.sub.1   R.sub.2  m.p.                                             ______________________________________                                        10A-1     CH.sub.2 Cl                                                                             CH.sub.3 171-173° C.                               10A-2     CH.sub.2 Cl                                                                             C.sub.2 H.sub.5                                                                        197-200° C.                                                            (THF/hexane)                                     10A-3     CH.sub.2 SCH.sub.3                                                                      C.sub.2 H.sub.5                                                                        137.5-138° C.                                                          (ether/hexane)                                   10A-4     CH.sub.2 Cl                                                                             C.sub.4 H.sub.9                                                                        99.5-102° C.                                                           (THF/hexane)                                     10A-5     CH.sub.2 Cl                                                                             iso-C.sub.3 H.sub.7                                                                    183.5-184.5° C.                                                        (THF/hexane)                                      10A-6*   CH.sub.2 Cl                                                                             iso-C.sub.4 H.sub.9                                                                    140-141° C.                                                            (THF/isopropyl ether)                            ______________________________________                                         *utilizing isobutyl chloroformate as the alkyl chloroformate reactant    

EXAMPLE 10B

The procedure of each paragraph of Example 2 is substantially repeated,substituting an equivalent quantity of each of the following startingmaterials for the steroids employed therein: methylthiomethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate; andmethylfulfonylmethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate. The following softanti-inflammatory agents of formula (I) are obtained.

    ______________________________________                                         ##STR223##                                                                   Compound No.    R.sub.1       R.sub.2                                         ______________________________________                                        10B-1           CH.sub.2 SCH.sub.3                                                                          CH.sub.3                                        10B-2           CH.sub.2 SCH.sub.3                                                                          C.sub.4 H.sub.9                                 10B-3           CH.sub.2 SCH.sub.3                                                                          i-C.sub.3 H.sub.7                               10B-4           CH.sub.2 SO.sub.2 CH.sub.3                                                                  CH.sub.3                                        10B-5           CH.sub.2 SO.sub.2 CH.sub.3                                                                  C.sub.2 H.sub.5                                 10B-6           CH.sub.2 SO.sub.2 CH.sub.3                                                                  C.sub.4 H.sub.9                                 10B-7           CH.sub.2 SO.sub.2 CH.sub.3                                                                  i-C.sub.3 H.sub.7                               ______________________________________                                    

Other representative species, e.g. compounds of Examples 7A and 7B, canlikewise be prepared according to the procedures of Examples 8 through10.

EXAMPLE 11

The products of Example 2 and Example 6A-4 are each allowed to react,first with diethylchlorophosphate and then with CH₃ SNa in chloroformfor approximately 6 hours. The following intermediates are obtained inthe first step:

    ______________________________________                                         ##STR224##                                                                   R.sub.2  R.sub.3         R.sub.4                                                                             Δ                                        ______________________________________                                        CH.sub.3 H               H     4                                              C.sub.2 H.sub.5                                                                        H               H     4                                              C.sub.4 H.sub.9                                                                        H               H     4                                              i-C.sub.3 H.sub.7                                                                      H               H     4                                              C.sub.2 H.sub.5                                                                        α-CH.sub.3                                                                              F     1,4                                            ______________________________________                                         and the following compounds of formula (I) are obtained in the second     step:

    ______________________________________                                         ##STR225##                                                                   R.sub.2  R.sub.3         R.sub.4                                                                             Δ                                        ______________________________________                                        CH.sub.3 H               H     4                                              C.sub.2 H.sub.5                                                                        H               H     4                                              C.sub.4 H.sub.9                                                                        H               H     4                                              i-C.sub.3 H.sub.7                                                                      H               H     4                                              C.sub.2 H.sub.5                                                                        α-CH.sub.3                                                                              F     1,4                                            ______________________________________                                    

When the remaining products of Example 6A and those of Example 6B aretreated according to the above procedure, the corresponding compounds ofthe formula ##STR226## wherein the various structural parametersrepresented by R₂, R₃, R₄, R₅, Z and the dotted line are identical tothose of compounds 6A1-6A3, 6A5-6A11, and 6B1-6B25 of Examples 6A and 6Bare obtained.

EXAMPLE 12

Chloromethyl 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate (0.01mol) is dissolved in toluene (100 milliliters) and the solution iscooled to approximately 0° C. Phosgene is then bubbled into thesolution, while maintaining the reaction mixture at low temperature,until the reaction is complete (approximately 2 hours). The solvent andexcess phosgene are removed by evaporation to leave the crude17α-chlorocarbonyloxy compound of the formula ##STR227##

The intermediate (0.01 mol) obtained above is then combined with ethanol(0.02 mol) containing 2,6-dimethylpyridine (0.01 mol) and allowed toreact at room temperature for 6 hours. At the end of that time, thedesired chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate isisolated from the reaction mixture. The compound melts at 197°-200° C.,after crystallization.

Substitution of an equivalent quantity of methylthiomethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate for the chloromethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate used above andsubstantial repetition of the foregoing procedure affordsmethylthiomethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,melting at 133°-136° C., after crystallization. That compound can then,if desired, be converted to the corresponding sulfonyl or sulfinylcompound as described in Example 4.

Other representative species, e.g., the compounds of Example 3,paragraphs 1, 3, 4 and 5, and the compounds of Examples 7A and 7B can beprepared in like manner from reaction of the corresponding 17α-hydroxy17β-carboxylates with the appropriate alcohols, including, whenappropriate, subsequent treatment with m-chloroperoxybenzoic acid as inExample 4.

EXAMPLE 13

The procedure of the first paragraph of Example 12 is repeated, exceptthat an equivalent quantity of11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid is used in placeof the chloromethyl 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate.The crude intermediate thus obtained has the formula ##STR228##

That intermediate is then subjected to the procedure of the secondparagraph of Example 12, to afford17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acid,identical to the product of Example 2, paragraph 2.

The other compounds of Examples 2, 6A and 6B can be prepared using thesame general procedure.

EXAMPLE 14

Chloromethyl 11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate (0.02mol) is combined with diethylcarbonate (0.2 mol) containing 20 mg ofp-toluenesulfonic acid. The reaction mixture is maintained at roomtemperature for 4 hours, then heated to about 80° to 85° C.; theremaining ethanol which forms is removed by distillation under reducedpressure. Obtained as the residue is crude chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,melting at 197°-200° C., after crystallization.

Substitution of an equivalent quantity of methylthiomethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate for the chloromethyl11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylate used above andsubstantial repetition of the foregoing procedure affordsmethylthiomethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,melting at 133°-136° C. That compound can then, if desired, be convertedto the corresponding sulfonyl or sulfinyl compound as described inExample 4.

Other representative species, e.g., the compounds of Example 3,paragraphs, 1, 3, 4 and 5, and the compounds of Examples 7A and 7B, canbe prepared in like manner from reaction of the corresponding17α-hydroxy-17β-carboxylates with the appropriate carbonates of the type##STR229## (including, when appropriate, subsequent treatment withm-chloroperoxybenzoic acid as in Example 4).

EXAMPLE 15

To a solution of 8.7 grams of11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid and 9.6milliliters of triethylamine in 100 milliliters of dry dichloromethane,is added 10 grams of ethyl chloroformate, dropwise at 0° to 5° C. Thereaction mixture is gradually allowed to warm to room temperature andthe insoluble material is removed by filtration. The filtrate is washedsuccessively with 3% aqueous sodium bicarbonate, 1% hydrochloric acid,and water, then is dried over anhydrous magnesium sulfate. The solventis concentrated under reduced pressure and the residue is crystallizedto give 10.5 grams of ethoxycarbonyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,melting at 158°-159° C.

EXAMPLE 16

Following the general method described in Example 15 and substitutingtherein the appropriate reactants affords the following additionalcompounds:

    ______________________________________                                         ##STR230##                                                                   Com-                                                                          pound                                                                         No.    R.sub.2     R.sub.3                                                                             R.sub.4                                                                           R.sub.5                                                                           Δ                                                                           melting point                            ______________________________________                                        16-A   CH.sub.2 CH.sub.3                                                                         H     F   H   4   110-111° C. (THF-                                                      isopropyl ether)                         16-B   iso-C.sub.3 H.sub.7                                                                       H     H   H   4   200-203° C.                       16-C   CH.sub.2 CH.sub.2 CH.sub.3                                                                H     H   H   4   142-143° C.                       ______________________________________                                                                             (THF)                                

EXAMPLE 17

To a solution of 9.8 grams of ethoxycarbonyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate in100 milliliters of tetrahydrofuran and 120 milliliters of ethanol areadded 42 milliliteres of 5% aqueous sodium becarbonate. The mixture isstirred at room temperature for about 30 hours and adjusted to pH 2 to 3by adding 1N hydrochloric acid. The insoluble material is isolated byfiltration. Recrystallization from a mixture of tetrahydrofuran andn-hexane gives 6 grams of17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acidhaving a melting point of 192°-195° C.

The compound obtained in Example 2, first paragraph, and the compoundsof Example 6A can be prepared, following the same procedure as above andsubstituting therein appropriate reactants.

EXAMPLE 18

Following the general method described in Example 17 and substitutingtherein the appropriate reactants affords the following compounds:

    ______________________________________                                         ##STR231##                                                                   Compound No.                                                                            R          melting point                                            ______________________________________                                        18-A                                                                                     ##STR232##                                                                              144.5-146.5° C. (THF/hexane)                      18-B      (CH.sub.2).sub.3 CH.sub.3                                                                164-166° C. (THF/hexane)                          ______________________________________                                    

EXAMPLE 19

To a solution of 8.7 grams of11β,17α-dihydroxyandrost-4-en-3-one-17β-carboxylic acid and 10 grams oftriethylamine in 100 milliliters of dichloromethane, a solution of 13.2grams of n-propyl chloroformate in 20 milliliters of dichloromethane isadded dropwise over 1-1.5 hours with ice-cooling. The reaction mixtureis allowed to warm to room temperature over a 2 hour period, then iswashed successively with 3% aqueous sodium bicarbonate, 1N hydrochloricacid, and water and dried over anhydrous sodium sulfate. The solvent isconcentrated under reduced pressure. Crystallization from a mixture ofether and n-hexane gives 10.5 grams of propoxycarbonyl11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate,which is dissolved in 40 milliliters of pyridine. To that solution, 300milliliters of water are added dropwise over a 1 to 1.5 hour period. Themixture is stirred for one hour and adjusted to pH 2 to 2.5 by addingconcentrated hydrochloric acid with ice-cooling. The mixture is thenextracted with chloroform, washed successively with 1N hydrochloric acidand water, and then dried over sodium sulfate. The solvent isconcentrated under reduced pressure, and the residue is recrystallizedfrom a mixture of acetone and tetrahydrofuran to give 7.7 grams of11β-hydroxy-17α-propoxycarbonyloxyandrost-4-en-3-one-17β-carboxylicacid, melting at 156°-157° C.

EXAMPLE 20

Following the general procedure detailed in Example 19, but utilizingthe appropriate starting materials and reaction conditions, affords theremaining compounds of Example 6A.

EXAMPLE 21

Chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate(2 grams) is dissolved in anhydrous dichloromethane (200 milliliters)and pyridinium chlorochromate (3.5 grams) is added at room temperature,with stirring. The resultant mixture is stirred for 24 hours, then thesolvent is concentrated under reduced pressure at about 10° to 20° C.The residue is subjected to column chromatography on silica gel (Kieselgel 60), using chloroform as an eluting solvent, followed byrecrystallization from a mixture of tetrahydrofuran and isopropyl etherto give chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-16α-methylandrosta-1,4-dien-3,11-dione-17β-carboxylate,in the yield of 1.7 grams, melting at 138°-140° C.

EXAMPLE 22

By a method similar to that described in Example 21, there is obtainedchloromethyl9α-fluoro-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-dien-3,11-dione-17β-carboxylate,melting at 200°-201° C.

EXAMPLE 23

Utilizing the general procedure of Example 3, but substituting theappropriate reactants therein, affords methyl17α-(2-chloroethoxy)carbonyloxy-9α-fluoro-11β-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17β-carboxylate.That product, after recrystallization from isopropanol, melts at223°-227° C.

EXAMPLE 24

In the same general manner as in Example 3, there is obtained2-chloroethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate.That product, after recrystallization from tetrahydrofuran-hexane, meltsat 243°-245° C.

EXAMPLE 25

Chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate(0.01 mol) and 1,2-dikmethylpyrrolidine (0.01 mol) are dissolved inacetonitrile (80 milliliters), and heated to the reflux temperature. Thereaction mixture is maintained at that temperature, with stirring, forapproximately 4 hours. About 65 ml of acetonitrile are removed; then,the mixture is cooled to room temperature and excess ethyl ether isadded to cause precipitation. The precipitate is separated byfiltration, washed, and dried in vacuo, thus affording the desiredquaternary ammonium salt of the formula ##STR233##

In analogous fashion, use of the appropriate steroidal and aminestarting materials in the foregoing general procedure affords thefollowing additional quaternary ammonium salts of the invention

    ______________________________________                                         ##STR234##                                                                    R.sub.2                                                                                  ##STR235##                                                        ______________________________________                                        CH.sub.3                                                                                  ##STR236##                                                        i-C.sub.3 H.sub.7                                                                        N(C.sub.2 H.sub.5).sub.3                                           C.sub.4 H.sub.9                                                                           ##STR237##                                                        C.sub.2 H.sub.5                                                                           ##STR238##                                                        C.sub.2 H.sub.5                                                                           ##STR239##                                                        C.sub.2 H.sub.5                                                                          N(C.sub.2 H.sub.5).sub.3                                           C.sub.2 H.sub.5                                                                           ##STR240##                                                        ______________________________________                                    

EXAMPLE 26

    ______________________________________                                        Ointment                                                                      Compound of formula (I),                                                                            0.2%     w/w                                            e.g. chloromethyl 17α-                                                  ethoxycarbonyloxy-11β-                                                   hydroxyandrost-4-en-                                                          3-one-17β-carboxylate or                                                 chloromethyl 11β-hydroxy-                                                17α-isopropoxycarbonyl-                                                 oxyandrost-4-en-3-one-                                                        17β-carboxylate                                                          Liquid paraffin       10.0%    w/w                                            White soft paraffin   89.8%    w/w                                            Aphthous Ulcer Pellet                                                         Compound of formula (I),                                                                            0.25     mg                                             as above                                                                      Lactose               69.90    mg                                             Acacia                3.00     mg                                             Magnesium stearate    0.75     mg                                             Retention Enema                                                               Compound of formula (I),                                                                            0.001%   w/v                                            as above                                                                      Tween 80              0.05%    w/v                                            Ethanol               0.015%   w/v                                            Propylparaben         0.02%    w/v                                            Methylparaben         0.08%    w/v                                            Distilled water       q.s. 100 volumes                                        Eye Drops                                                                     Compound of formula (I),                                                                            0.1%     w/v                                            as above                                                                      Tween 80              2.5%     w/v                                            Ethanol               0.75%    w/v                                            Benalkonium chloride  0.02%    w/v                                            Phenyl ethanol        0.25%    w/v                                            Sodium chloride       0.60%    w/v                                            Water for injection   q.s. 100 volumes                                        ______________________________________                                    

EXAMPLE 27

    ______________________________________                                        Ointment                                                                      Compound of formula (I),                                                                            0.025%    w/w                                           e.q. chloromethyl 17α-                                                  ethoxycarbonyloxy-9α-                                                   fluoro-11β-hydroxy-16α-                                            methylandrosta-1,4-dien-                                                      3-one-17β-carboxylate or                                                 chloromethyl 9α-fluoro-                                                 11β-hydroxy-17α-                                                   methoxycarbonyloxy-16α-                                                 methylandrosta-1,4-dien-                                                      3-one-17β-carboxylate                                                    Liquid paraffin       10.175%   w/w                                           White soft paraffin   89.8%     w/w                                           Aphthous Ulcer Pellet                                                         Compound of formula (I),                                                                            0.1       mg                                            e.g. chloromethyl 9α-fluoro-                                            11α-hydroxy-17α-                                                  isopropoxycarbonyloxy-16β-                                               methylandrosta-1,4-dien-3-                                                    one-17β-carboxylate or                                                   chloromethyl 17α-                                                       ethoxycarbonyloxy-9α-fluoro-                                            11β-hydroxy-16α-                                                   methylandrosta-1,4-dien-3-                                                    one-17β-carboxylate                                                      Lactose               69.90     mg                                            Acacia                3.00      mg                                            Magnesium stearate    0.75      mg                                            Retention Enema                                                               Compound of formula (I),                                                                            0.001%    w/v                                           e.g. chloromethyl 11β-                                                   hydroxy-17α-                                                            isopropoxycarbonyloxy-                                                        androsta-1,4-dien-3-one-                                                      17β-carboxylate or                                                       chloromethyl 9α-fluoro-                                                 11β-hydroxy-17α-                                                   isopropoxycarbonyloxy-                                                        16β-methylandrosta-1,4-                                                  dien-3-one-17β-carboxylate                                               Tween 80              0.05%     w/v                                           Ethanol               0.015%    w/v                                           Propylparaben         0.02%     w/v                                           Methylparaben         0.08%     w/v                                           Distilled water       q.s. 100 volumes                                        Eye Drops                                                                     Compound of formula (I),                                                                            0.025%    w/v                                           e.g. chloromethyl 9α-                                                   fluoro-11β-hydroxy-16α-                                            methyl-17α-propoxy-                                                     carbonyloxyandrosta-1,4-                                                      dien-3-one-17β-carboxylate                                               or chloromethyl 9α-fluoro-                                              11β-hydroxy-17α-methoxy-                                           carbonyloxy-16α-methyl-                                                 androsta-1,4-dien-3-one-                                                      17β-carboxylate                                                          Tween 80              2.5%      w/v                                           Ethanol               0.75%     w/v                                           Benzalkonium chloride 0.02%     w/v                                           Phenyl ethanol        0.25%     w/v                                           Sodium chloride       0.60%     w/v                                            Water for injection  q.s. 100 volumes                                        ______________________________________                                    

EXAMPLE 28

To a solution of 3 grams of chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylatein 100 ml of acetonitrile, 7.9 grams of AgF (a 10:1 molar ratio of AgFto steriod) are added, and the mixture is stirred at room temperaturefor 12 days while shading the reaction system for light. Thereafter, thereaction mixture is filtered, and the solid on the filter is fullywashed with ethyl acetate. The filtrate and the ethyl acetate solutionare combined, and the mixture is washed with water and a saturatedaqueous sodium chloride solution, and dried over anhydrous sodiumsulfate. The solvents are distilled off, giving 2 grams of crudecrystalline product. The product is subjected to preparative thin-layerchromatography (Silica Gel 60F254, Merck), using a mixture of chloroformand methanol (15:1) as an eluting solvent. Then the product isrecrystallized from a mixture of tetrahydrofuran and n-hexane to give180 mg of fluoromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylateas colorless needles, melting at 207.5°-210° C.

EXAMPLE 29

Following the general procedure of Example 28 and substituting thereinthe appropriate reactants affords the following compounds: ##STR241##

    __________________________________________________________________________    Compound                                                                      No.   R.sub.1                                                                            R.sub.2 R.sub.3                                                                           R.sub.4                                                                         R.sub.5                                                                         Z     Δ                                                                         mp                                         __________________________________________________________________________    29-1  CH.sub.2 F                                                                         C.sub.2 H.sub.5                                                                       α-CH.sub.3                                                                  F H                                                                                     1,4                                                                             239-240.5° C. (THF/hexane)          29-2  CH.sub.2 F                                                                         CH.sub.2 CH.sub.2 CH.sub.3                                                            α-CH.sub.3                                                                  F H                                                                                ##STR242##                                                                         1,4                                                                             165-165.5° C. (THF/hexane)          __________________________________________________________________________

The foregoing compounds can be named as follows:

29-1: fluoromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate

29-2: fluoromethyl9α-fluoro-11β-hydroxy-16α-methyl-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate

From the foregoing description, one of ordinary skill in the art canreadily ascertain the essential characteristics of the present inventionand, without departing from the spirit and scope thereof, can makevarious changes in and/or modifications of the invention to adapt it tovarious usages and conditions. As such, these changes and/ormodifications are properly, equitably and intended to be within the fullrange of equivalence of the following claims.

What is claimed is:
 1. A compound selected from the group consistingof:(a) a compound of the formula ##STR243## wherein: R₁ is C₁ -C₁₀alkyl; C₂ -C₁₀ (monohydroxy or polyhydroxy)alkyl; C₁ -C₁₀ (monohalo orpolyhalo)alkyl; or --CH₂ COOR₆ wherein R₆ is unsubstituted orsubstituted C₁ -C₁₀ alkyl; C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl or C₂-C₁₀ alkenyl, the substituents being selected from the group consistingof halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, loweralkylsulfonyl, ##STR244## or R₆ is unsubstituted or substituted phenylor benzyl, the substituents being selected from the group consisting oflower alkyl, lower alkoxy, halo, carabamoyl, lower alkoxycarbonyl, loweralkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(loweralkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, loweralkylthio, lower alkylsulfinyl and lower alkylsulfonyl; or R₁ is --CH₂CONR₇ R₈ wherein R₇ and R₈, which can be the same or different, are eachhydrogen, lower alkyl, C₃ -C₈ cycloalkyl, phenyl or benzyl, or R₇ and R₈are combined such that --NR₇ R₈ represents the residue of a saturatedmonocyclic secondary amine; or R₁ is unsubstituted or substituted phenylor benzyl, the substituents being selected from the group of phenyl andbenzyl substituents defined hereinabove with respect to R₆ ; or R₁ is##STR245## wherein Y is --S--, --SO--, --SO₂ -- or --O-- and R₉ ishydrogen, lower alkyl or phenyl, or R₉ and the lower alkyl groupadjacent to Y are combined so that R₁ is a cyclic system of the type##STR246## wherein Y is defined as above and the alkylene group contains3 to 10 carbon atoms, of which at least 3 and no more than 6 are ringatoms; or R₁ is ##STR247## wherein R₆ is defined as hereinabove and R₁₀is hydrogen, lower alkyl, phenyl or halophenyl;R₂ is unsubstituted orsubstituted C₁ -C₁₀ alkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkenyl or C₂-C₁₀ alkenyl, the substituents being selected from the group consistingof halo, lower alkoxy, lower alkylthio, lower alkylsulfinyl, loweralkylsulfonyl, ##STR248## or R₂ is unsubstituted or substituted phenylor benzyl, the substituents being selected from the group consisting oflower alkyl, lower alkoxy, halo, carbamoyl, lower alkoxycarbonyl, loweralkanoyloxy, lower haloalkyl, mono(lower alkyl)amino, di(loweralkyl)amino, mono(lower alkyl)carbamoyl, di(lower alkyl)carbamoyl, loweralkylthio, lower alkylsulfinyl and lower alkylsulfonyl; R₃ is hydrogen,α-hydroxy, β-hydroxy, α-methyl, β-methyl, ═CH₂, or α- or ##STR249##wherein R₂ is identical to R₂ as defined hereinabove; R₄ is hydrogen,fluoro or chloro; R₅ is hydrogen, fluoro, chloro or methyl; X is --O--or --S--; and the dotted line in ring A indicates that the 1,2 linkageis saturated or unsaturated; (b) a quaternary ammonium salt of acompound of formula (I) wherein at least one of R₁ and R₂ is ahalo-substituted alkyl group; (c) a compound of the formula ##STR250##wherein R₂, R₄, R₅, and the dotted line in ring A are as defined in (a)above, Z is carbonyl or β-hydroxymethylene and R₃ " is hydrogen,α-methyl, β-methyl, ═CH₂ or α- or ##STR251## wherein R₂ is identical toR₂ above; (d) a compound of the formula ##STR252## wherein M is alkalimetal, thallium, alkaline earth metal/2 or NH₄ and R₂, R₃ ", R₄, R₅, Zand the dotted line in ring A are as defined in (a) and (c) above; (e) acompound of the formula ##STR253## wherein R₃ "' is hydrogen, α-methyl,β-methyl, α-OCOCl or β-OCOCl, and R₁, R₄, R₅, Z and the dotted line inring A are as defined in (a) and (c) above; (f) a compound of theformula ##STR254## wherein R₂, R₃ ", R₄, R₅, Z and the dotted line inring A are as defined in (a) and (c) above; and (g) a compound of theformula ##STR255## wherein R₁, R₂, R₃, R₄, R₅, X and the dotted line inring A are as defined in (a) above.
 2. A compound selected from thegroup consisting of:(a) a compound of the formula ##STR256## wherein: R₁is C₁ -C₆ alkyl; C₁ -C₆ (monohalo or polyhalo)alkyl; --CH₂ COOR₆ whereinR₆ is C₁ -C₆ alkyl; --CH₂ --Y--(C₁ -C₆ alkyl) wherein Y is --S--,--SO--, --SO₂ -- or --O--; or ##STR257## wherein R₆ ' is C₁ -C₆ orphenyl; R₂ is C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, phenyl, benzyl or C₁ -C₆(monohalo or polyhalo)alkyl;R₃ is hydrogen, α-hydroxy, β-methyl,β-methyl or ##STR258## wherein R₂ is identical to R₂ as definedhereinabove; R₄ is hydrogen or fluoro; R₅ is hydrogen or fluoro; X is--O--; and the dotted line in ring A indicates that the 1,2-linkage issaturated or unsaturated; (b) a quaternary ammonium salt of a compoundof formula (I) wherein at least one of R₁ and R₂ is a halo-substitutedalkyl group; (c) a compound of the formula ##STR259## wherein R₂, R₄, R₅and the dotted line in ring A are as defined in (a) above, Z is carbonylor β-hydroxymethylene and R₃ " is hydrogen, α-methyl, β-methyl or##STR260## wherein R₂ is identical to R₂ above; (d) a compound of theformula ##STR261## wherein M is alkali metal, thallium, alkaline earthmetal/2 or NH₄ and R₂, R₃ ", R₄, R₅, Z and the dotted line in ring A areas defined in (a) and (c) above; (e) a compound of the formula##STR262## wherein R₃ "' is hydrogen, α-methyl, β-methyl or α-OCOCl, andR₁, R₄, R₅, Z and the dotted line in ring A are as defined in (a) and(c) above; (f) a compound of the formula ##STR263## wherein R₂, R₃ ",R₄, R₅, Z and the dotted line in ring A are as defined in (a) and (c)above; and (g) a compound of the formula ##STR264## wherein R₁, R₂, R₃,R₄, R₅, X and the dotted line in ring A are as defined in (a) above. 3.A compound of claim 1 or 2, said compound having the structural formula(I).
 4. A compound of claim 1 or 2, said compound being a quaternaryammonium salt of a compound of formula (I) wherein at least one of R₁and R₂ is a halo-substituted alkyl group.
 5. A compound of claim 1 or 2,said compound having the structural formula (III).
 6. A compound ofclaim 1 or 2, said compound having the structural formula (IV).
 7. Acompound of claim 1 or 2, said compound having the structural formula(VII).
 8. A compound of claim 1 or 2, said compound having thestructural formula (VIII).
 9. A compound of claim 1 or 2, said compoundhaving the structural formula (IX).
 10. A compound of claim 1, saidcompound having the structural formula (I) wherein R₃ is hydrogen,α-methyl, β-methyl, ═CH₂ or α- or ##STR265##
 11. A compound of claim 1or 2, said compound having the structural formula (I) wherein R₁ is C₁-C₆ alkyl.
 12. A compound of claim 1 or 2, said compound having thestructural formula (I) wherein R₁ is C₁ -C₆ (monohalo or polyhalo)alkyl.13. A compound of claim 12 wherein C₁ -C₆ (monohalo or polyhalo)alkyl isC₁ -C₆ monohaloalkyl.
 14. A compound of claim 13 wherein C₁ -C₆monohaloalkyl is C₁ -C₆ monochloroalkyl.
 15. A compound of claim 14wherein C₁ -C₆ monochloroalkyl is chloromethyl.
 16. A compound of claim11 wherein R₂ is C₁ -C₆ alkyl or C₁ -C₆ monohaloalkyl.
 17. A compound ofclaim 12 wherein R₂ is C₁ -C₆ alkyl.
 18. A compound of claim 13 whereinR₂ is C₁ -C₆ alkyl.
 19. A compound of claim 14 wherein R₂ is C₁ -C₆alkyl.
 20. A compound of claim 15 wherein R₂ is C₁ -C₆ alkyl.
 21. Acompound of claim 11 wherein R₂ is C₃ -C₈ cycloalkyl, phenyl, benzyl orC₁ -C₆ (monohalo or polyhalo)alkyl.
 22. A compound of claim 12 whereinR₂ is C₃ -C₈ cycloalkyl, phenyl, benzyl or C₁ -C₆ (monohalo orpolyhalo)alkyl.
 23. A compound of claim 13 wherein R₂ is C₃ -C₈cycloalkyl, phenyl, benzyl or C₁ -C₆ (monohalo or polyhalo)alkyl.
 24. Acompound of claim 14 wherein R₂ is C₃ -C₈ cycloalkyl, phenyl, benzyl orC₁ -C₆ (monohalo or polyhalo)alkyl.
 25. A compound of claim 15 whereinR₂ is C₃ -C₈ cycloalkyl, phenyl, benzyl or C₁ -C₆ (monohalo orpolyhalo)alkyl.
 26. A compound of claim 1, said compound having thestructural formula (I) wherein X is --O--.
 27. A compound of claim 12wherein X is --O--.
 28. A compound of claim 13 wherein X is --O--.
 29. Acompound of claim 14 wherein X is --O--.
 30. A compound of claim 17wherein R₄ and R₅ are hydrogen.
 31. A compound of claim 18 wherein R₄and R₅ are hydrogen.
 32. A compound of claim 19 wherein R₄ and R₅ arehydrogen.
 33. A compound of claim 20 wherein R₄ and R₅ are hydrogen. 34.A compound of claim 17 wherein at least one of R₄ and R₅ is fluoro. 35.A compound of claim 18 wherein at least one of R₄ and R₅ is fluoro. 36.A compound of claim 19 wherein at least one of R₄ and R₅ is fluoro. 37.A compound of claim 20 wherein at least one of R₄ and R₅ is fluoro. 38.A compound of claim 17 wherein R₄ is fluoro and R₅ is hydrogen.
 39. Acompound of claim 18 wherein R₄ is fluoro and R₅ is hydrogen.
 40. Acompound of claim 19 wherein R₄ is fluoro and R₅ is hydrogen.
 41. Acompound of claim 20 wherein R₄ is fluoro and R₅ is hydrogen.
 42. Acompound of claim 35 wherein R₃ is α-methyl or β-methyl.
 43. A compoundof claim 37 wherein R₃ is α-methyl or β-methyl.
 44. A compound of claim39 wherein R₃ is α-methyl or β-methyl.
 45. A compound of claim 41wherein R₃ is α-methyl or β-methyl.
 46. A compound of claim 1 or 2, saidcompound having the structural formula (I) wherein R₁ is --CH₂ COOR₆,--CH₂ --Y--(C₁ -C₆ alkyl) or ##STR266##
 47. A compound of claim 1, saidcompound having the structural formula (I) wherein R₁ is --CH₂ CONR₇ R₈.48. A compound of claim 47 wherein at least one of R₇ and R₈ is hydrogenor C₁ -C₆ alkyl.
 49. A compound of claim 47 wherein R₇ and R₈ arecombined so that --NR₇ R₈ represents the residue of a saturatedmonocyclic secondary amine containing 5 to 7 carbon atoms.
 50. Acompound of claim 49 wherein --NR₇ R₈ representss morpholino,1-pyrrolidinyl, 4-benzyl-1-piperazinyl, perhydro-1,2,4-oxathiazin-4-yl,1- or 4-piperazinyl, 4-methyl-1-piperazinyl, piperidino,hexamethyleneimino, 4-phenylpiperidino, 2-methyl-1-pyrazolidinyl, 1- or2-pyrazolidinyl, 3-methyl-1-imidazolidinyl, 1- or 3-imidazolidinyl,4-benzylpiperidino or 4-phenyl-1-piperazinyl.
 51. A compound of claim 1,said compound having the structural formula (I) wherein R₁ is ##STR267##wherein R₉ is hydrogen or methyl, or wherein R₉ and the lower alkylgroup adjacent to Y are combined so that R₁ is ##STR268## wherein Y is--S--, --SO--, --SO₂ -- or --O-- and the alkylene group contains 3 to 10carbon atoms, of which at least 3 and no more than 6 are ring atoms. 52.A compound of claim 1 or 2, said compound having the structural formula(III) wherein Z is β-hydroxymethylene and R₂ is C₁ -C₆ alkyl.
 53. Acompound of claim 1 or 2, said compound having the structural formula(IV) wherein Z is β-hydroxymethylene and R₂ is C₁ -C₆ alkyl.
 54. Acompound of claim 1 or 2, said compound having the structural formula(VII) wherein Z is β-hydroxymethylene and R₁ is C₁ -C₆ alkyl or C₁ -C₆monohaloalkyl.
 55. A compound of claim 1 or 2, said compound having thestructural formula (VIII) wherein Z is β-hydroxymethylene and R₂ is C₁-C₆ alkyl.
 56. A compound of claim 1 or 2, said compound having thestructural formula (IX) wherein R₁ is C₁ -C₆ (monohalo or polyhalo)alkyl.
 57. A compound of claim 56 wherein C₁ -C₆ (monohalo orpolyhalo)alkyl is C₁ -C₆ monohaloalkyl.
 58. A compound of claim 57wherein R₂ is C₁ -C₆ alkyl.
 59. A compound of claim 1 or 2, saidcompound having the structural formula (IX) wherein R₁ is C₁ -C₆ alkylor C₁ -C₆ monohaloalkyl, R₂ is C₁ -C₆ alkyl or C₁ -C₆ monohaloalkyl andX is --O--.
 60. A compound of claim 2, said compound having thestructural formula (IX) wherein R₁ is C₁ -C₆ alkyl, --CH₂ COOR₆, --CH₂--Y--(C₁ -C₆ alkyl) or ##STR269##
 61. The compound of claim 2 which ischloromethyl11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate.62. The compound of claim 2 which is chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate. 63.The compound of claim 2 which is chloromethyl17β-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate. 64.The compound of claim 2 which is chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate.65. The compound of claim 2 which is chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylate.66. The compound of claim 2 which is chloromethyl9α-fluoro-11β-hydroxy-16α-methyl-17α-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate.67. The compound of claim 2 which is 1-chloroethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate.68. The compound of claim 2 which is 1-chloroethyl9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylate.69. The compound of claim 2 which is chloromethyl17α-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17.beta.-carboxylate.70. The compound of claim 2 which is chloromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate.71. The compound of claim 2 which is chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate.72. The compound of claim 2 which is chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate.73. The compound of claim 2 is chloromethyl9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate.74. The compound of claim 2 which is chloromethyl9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylate.75. The compound of claim 2 which is chloromethyl9α-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylate.76. The compound of claim 2 which is chloromethyl9α-fluoro-11β-hydroxy-16α-methyl-17α-pentyloxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate.77. The compound of claim 2 which is fluoromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate.78. The compound of claim 2 which is methyl17α-(2-chloroethoxy)carbonyloxy-9α-fluoro-11β-hydroxy-16.alpha.-methylandrosta-1,4-dien-3-one-17β-carboxylate.79. The compound of claim 2 which is17β-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicacid.
 80. The compound of claim 2 which is9α-fluoro-11β-hydroxy-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-dien-3-one-17β-carboxylicacid.
 81. The compound of claim 2 which is9α-fluoro-11β-hydroxy-16α-methyl-17α-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylicacid.
 82. The compound of claim 2 which is9α-fluoro-11β-hydroxy-17α-methoxycarbonyloxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylicacid.
 83. The compound of claim 2 which is11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylicacid, 17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylicacid, 17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylicacid, or11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylicacid.
 84. The compound of claim 2 which is sodium11β-hydroxy-17α-methoxycarbonyloxyandrost-4-en-3-one-17β-carboxylate,sodium17α-ethoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate,sodium17α-butoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate, orsodium11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate.85. The compound of claim 2 which is chloromethyl17α-chlorocarbonyloxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylate. 86.The compound of claim 2 which is chloromethyl17α-ethoxycarbonyloxy-9α-fluoro-16α-methylandrosta-1,4-dien-3,11-dione-17β-carboxylate.87. The compound of claim 2 which is chloromethyl9α-fluoro-17α-isopropoxycarbonyloxy-16β-methylandrosta-1,4-diene-3,11-dione-17β-carboxylate.88. A pharmaceutical composition of matter comprising ananti-inflammatory effective amount of a compound of claim 1 or 2 havingthe structural formula (I), in combination with a non-toxicpharmaceutically acceptable carrier therefor suitable for topical orother local application.
 89. A method for alleviating inflammation in oron a warm-blooded animal exhibiting a topical inflammatory response,which comprises topically administering thereto an anti-inflammatoryeffective amount of a composition of claim
 88. 90. A method foralleviating inflammation in or on a warm-blooded animal exhibiting alocalized inflammatory response, which comprises locally administeringthereto an anit-inflammatory effective amount of composition of claim88.
 91. A compound of claim 13 wherein C₁ -C₆ monohaloalkyl is C₁≢-C₆monofluoroalkyl.
 92. A compound of claim 91 wherein C₁ -C₆monofluoroalkyl is fluoromethyl.
 93. A compound of claim 91 wherein R₂is C₁ -C₆ alkyl.
 94. A compound of claim 92 wherein R₂ is C₁ -C₆ alkyl.95. A compound of claim 91 wherein X is --I--.
 96. A compound of claim95 wherein R₄ and R₅ are hydrogen.
 97. A compound of claim 96 wherein R₃is hydrogen.
 98. A compound of claim 95 wherein at least one of R₄ andR₅ is fluoro.
 99. A compound of claim 95 wherein R₄ is fluoro and R₅ ishydrogen.
 100. A compound of claim 99 wherein R₃ is α-methyl orβ-methyl.
 101. A compound of claim 2 which is fluoromethyl11β-hydroxy-17α-isopropoxycarbonyloxyandrost-4-en-3-one-17.beta.-carboxylate.102. The compound of claim 2 which is fluoromethyl17α-ethoxycarbonyloxy-9α-fluoro-11β-hydroxy-16α-methylandrosta-1,4-dien-3-one-17β-carboxylate.103. The compound of claim 2 which is fluoromethyl9α-fluoro-11β-hydroxy-16α-methyl-17α-n-propoxycarbonyloxyandrosta-1,4-dien-3-one-17β-carboxylate.104. A compound of claim 1 or 2, said compound having the structuralformula (I) wherein R₃, R₄ and R₅ are hydrogen and the 1,2 linkage issaturated or unsaturated.
 105. A compound of claim 1 or 2, said compoundhaving the structural formula (I) wherein R₃ is selected from hydrogenor methyl, R₄ is fluoro and R₅ is hydrogen and the 1,2 linkage issaturated or unsaturated.
 106. A compound of claim 1 or 2, said compoundhaving the structural formula (I) wherein R₃ is hydrogen or methyl, R₄is hydrogen or fluoro and R₅ is fluoro or methyl and the 1,2 linkage isunsaturated.
 107. A compound of claim 1 or 2, said compound having thestructural formula (I) wherein R₃ is ##STR270## and wherein R₄ is fluoroand R₅ is hydrogen and the 1,2 linkage is unsaturated.
 108. A compoundof claim 59 wherein R₃ is hdyrogen or methyl, R₄ is hydrogen and R₅ ishydrogen or chloro and the 1,2 linkage is saturated or unsaturated. 109.The compound of claim 45 wherein R₃ is α-methyl and the 1,2 linkage isunsaturated.
 110. A compound of the formula ##STR271## wherein R₁ is C₁-C₆ (monohalo)alkyl, R₂ is C₁ -C₆ alkyl, R₃ is hydrogen, α-methyl orβ-methyl and R₄ is hydrogen or fluoro.
 111. A compound of claim 110wherein R₁ is chloromethyl.
 112. A compound of claim 110 wherein R₃ isα-methyl and R₄ is fluoro.
 113. A compound of the formula ##STR272##wherein: R₁ is --CH₂ COOR₆ wherein R₆ is C₁ -C₆ alkyl; --CH₂ --Y--(C₁-C₆ alkyl) wherein Y is --S--, --SO--, --SO₂ -- or --O--; or ##STR273##wherein R₆ ' is C₁ -C₆ alkyl or phenyl; R₂ is C₁ -C₆ alkyl, C₃ -C₈cycloalkyl, phenyl, benzyl or C₁ -C₆ (monohalo or polyhalo)alkyl;R₃ ishydrogen, α-hydroxy, α-methyl, β-methyl or ##STR274## wherein R₂ is asdefined above; R₄ is hydrogen or fluoro; R₅ is hydrogen or fluoro; X is--O-- or --S--; and the dotted line in ring A indicates that the1,2-linkage is saturated or unsaturated.